20S-proteasome May Be Useful Biomarker of AAV Disease Activity

The 20S-proteasome — the core of an enzyme complex responsible for eliminating unnecessary or damaged proteins in cells — may be a useful biomarker of disease activity in people with ANCA-associated vasculitis (AAV), a study shows.

The study, “Serum 20S proteasome levels are associated with disease activity in MPO-ANCA-associated microscopic polyangiitis,” was published in the journal BMC Rheumatology.

In addition to destroying unnecessary or damaged proteins, proteasomes are involved in cell differentiation and controlled cell death (apoptosis).

In some blood cancers, such as myeloma, levels of proteasomes in the blood are abnormally high, because these enzyme complexes are overproduced by cancer cells to cope with their fast metabolism. In these patients, proteasome levels are directly associated with disease activity and severity.

“Similarly, elevated serum proteasome levels were also reported in autoimmune diseases characterized by B-cell abnormality,” the researchers wrote. (B-cells are immune cells responsible for producing antibodies, including the ANCA antibodies involved in AAV.)

To investigate the potential usefulness of the proteasome as a biomarker of disease activity in AAV patients at different stages of the disease, researchers at Tokyo Medical University Ibaraki Medical Center measured the levels of its core complex — the 20S-proteasome — in the blood of 44 AAV patients.

All patients had kidney symptoms associated with their microscopic polyangiitis, and were positive for ANCA antibodies targeting the myeloperoxidase (MPO) protein. Of them, 30 provided blood samples before initiating treatment, 30 after entering in clinical remission, and 16 at both time points.

As controls, 14 healthy individuals and 26 patients with chronic kidney disease were enrolled.

Proteasome levels in AAV patients and controls were measured by enzyme-linked immunosorbent assay (ELISA), a technique that allows researchers to measure the levels of certain molecules using an enzymatic reaction.

Analyses showed the levels of 20S-proteasome were much higher in patients with active disease (3,414.6 nanograms per milliliter, or ng/mL), compared to those in clinical remission (366.4 ng/mL) and controls (234.9 ng/mL).

Among those with active disease, this biomarker also was significantly greater in patients with interstitial lung disease, which results in inflammation and irreversible scarring of the lungs, than in those without that lung disease.

Other measures, such as kidney impairment and inflammation, all were  greater in AAV patients with active disease than in controls or patients in remission. The amount of ANCA antibodies in circulation and disease activity — measured with the Birmingham Vasculitis Activity Score (BVAS) — also were greater in patients with active disease than in those in remission.

Statistical analyses found that the levels of 20S-proteasome were associated directly with BVAS scores, levels of ANCA autoantibodies, platelet and white blood cells counts, and levels of C-reactive protein (CRP, an inflammation marker).

However, in a subsequent statistical analysis, the levels of 20S-proteasome only correlated significantly with BVAS scores.

The researchers then established a level of 563.1 ng/mL of 20S-proteasome as the best cut-off value to distinguish patients with high and low disease activity. This cut-off was able to discriminate disease activity levels with high accuracy (99.6%).

It also was better than other blood markers of disease activity, such as white blood cell levels and CRP levels. CRP was better than 20S-proteasome levels at accurately detecting people with high disease activity, but worse at identifying those with low disease activity, researchers noted.

“The serum level of 20S-proteasome may therefore be a useful marker for disease activity in AAV,” the investigators concluded, adding that more studies are needed to discover the mechanisms leading to an increase in proteasome levels in these patients.