Complement System Plays Role in ANCA-associated Vasculitis, Regardless of ANCA Subtype, Study Says

Iqra Mumal, MSc avatar

by Iqra Mumal, MSc |

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blood biomarker study

The complement system, an important part of immunity, is activated in ANCA-associated vasculitis patients with myeloperoxidase (MPO) antibodies as well as those with proteinase 3 (PR3) ANCA antibodies, but its activation profile appears to differ by severity of disease and possibly by ANCA subtype, a new study shows.

The study, “Measuring circulating complement activation products in myeloperoxidase and proteinase 3 antineutrophil cytoplasmic antibody vasculitis,” was published in the journal Arthritis & Rheumatology.

Emerging evidence suggests that complement activation — a component of the immune system that helps fight foreign pathogens — plays a major role in the disease mechanisms that lead to the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

In particular, studies in mouse models of vasculitis have established the complement system as a critical factor for disease development and progression, particularly in the presence of MPO-ANCA antibodies. But the role of this system in PR3-ANCA-positive patients is far less understood.

To investigate that, researchers studied complement activation in 98 patients with either MPO-ANCA or PR3-ANCA vasculitis. Results were compared to those from 35 healthy controls.

One of the problems with measuring complement levels in a laboratory setting is that cleavage of complement proteins (which indicates complement activation) can occur even after the blood has been withdrawn, which can skew the results. Hence, futhan (an inhibitor of protein-degrading enzymes, which prevents complement proteins from being cleaved) is often added to the blood samples.

In their study, the researchers also aimed to determine the effects of futhan on the accurate measurement of complement activation in ANCA-vasculitis patients and healthy controls.

High levels of cleaved proteins — including Bb, C3a, C5a, sC5b‐9, properdin, and C4d — are indicative of complement activation. Thus, levels of these cleaved proteins were measured.

Results indicated that compared with healthy controls, C3a, C5a, and sC5b‐9 levels were significantly higher in patients with active MPO‐ANCA vasculitis. Additionally, levels of Bb, C3a, and sC5b‐9 remained higher in MPO‐ANCA patients in remission compared with healthy controls.

In patients with PR3‐ANCA vasculitis, levels of C3a, C5a, sC5b‐9, and C4d were significantly higher in patients with active disease, compared with healthy controls. Furthermore, C3a and C4d remained higher in patients in remission.

Interestingly, when comparing patients with active disease to those in remission, the researchers did not find any significant differences in levels of any cleaved complement protein, regardless of ANCA-subtype.

However, the researchers did find that levels of sC5b‐9 reduced significantly when a patient with active disease went into remission.

“Our study demonstrates that complement activation not only occurs in MPO-ANCA vasculitis, but also PR3-ANCA vasculitis. The complement activation profile differs by disease activity and may differ by ANCA serotype,” the researchers concluded.

They also found that levels of Bb, C5a, and sC5b‐9 were considerably higher for samples that had been processed without futhan, compared with samples with futhan, concluding that “futhan reduces in vitro complement activation and provides a more accurate measurement.”