Low C3 Levels at Diagnosis Can Predict Severity of ANCA-associated Vasculitis, Poor Kidney Outcomes, Study Finds

Low C3 Levels at Diagnosis Can Predict Severity of ANCA-associated Vasculitis, Poor Kidney Outcomes, Study Finds

Patients with ANCA-associated vasculitis (AAV) are more likely to exhibit severe disease and experience poor kidney outcomes if they have low levels of the C3 complement protein at diagnosis, a study found.

Researchers said the findings will help doctors identify AAV patients with severe disease and select appropriate treatment at the time of diagnosis.

The study, “Low serum complement 3 level is associated with severe ANCA-associated vasculitis at diagnosis,” was published in the journal Clinical and Experimental Nephrology.

The complement system is a major component of the immune system that helps fight infections. It becomes activated in the presence of invaders, such as bacteria, but studies suggest it also plays a fundamental role in AAV.

In the presence of ANCA antibodies — the hallmark of AAV — immune cells called neutrophils become overactive, leading to the blood vessel inflammation that characterizes the disease.

This causes the release of complement-activating factors, including molecules that break down the C3 protein into C3a and C3b. Eventually, a cycle is created where C3b causes more neutrophils to become active, which will contribute to the damage in AAV.

Because the C3 complement protein is cleaved during neutrophil activation, patients with lower C3 levels at diagnosis have poorer survival outcomes.

Researchers in Korea now aimed to determine whether low C3 levels at diagnosis can identify patients with severe disease, also at the time of diagnosis. Because use of immunosuppressive medicines may influence disease severity and immune system activation, researchers used a group of patients who had never received immunosuppressive drugs.

They examined the medical records of 139 patients with AAV (median age at diagnosis 56.3), including 41 men.

Patients with low C3 levels had cardiovascular disease more often (54.8%) than those with normal levels (20.4%), researchers found. They also had higher disease severity scores – measured with the Birmingham Vasculitis Activity Score — and poorer prognosis — assessed through the five-factor score.

C4, another protein of the complement system, showed a similar correlation with disease activity and prognostic scores.

Next, researchers divided patients in into two groups — low and normal C3 levels — “because low serum C3 level has more clinical implication than continuous serum C3 level,” they stated.

Additional analysis showed that patients with C3 levels below 90 mg/dl (the low group) at diagnosis were nearly three times more likely to have severe disease, compared to patients with C3 levels of 90 mg/dl or higher (the normal group).

Creatinine, a marker of kidney malfunction, was also closely associated with severe disease at diagnosis.

Patients in the low and normal C3 groups received similar treatment and were followed for roughly the same amount of time. Nevertheless, patients in the low C3 group were five times more likely to develop end-stage liver disease than those with normal C3 levels at diagnosis.

Survival rates, however, were similar for the two groups.

“Low serum C3 level can be an independent predictor of severe AAV and poor renal outcome in immunosuppressive drug-naïve patients at diagnosis,” researchers concluded.

“Therefore, we suggest that physicians should pay more attention to AAV patients with low serum C3 level, try not to miss the clue to imply the high severity of AAV and select the proper induction therapeutic regimens at the time of diagnosis of AAV,” they said.

For most AAV patients, initial laboratory tests already include C3 and C4, to rule out other autoimmune diseases such as lupus. “Thus, no additional medical costs are needed,” investigators said.

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