B-cells Marker Levels May Predict Complete Responses to Rituximab in GPA, MPA

High blood levels of FCRL5 — a protein mainly found in certain B-cells, a type of immune cell — are linked with a greater likelihood of achieving and maintaining a complete response to rituximab in people with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), a study shows.

These findings suggest that FCRL5 may be used as a biomarker in this patient population to predict and monitor responses to rituximab, which has been shown to induce disease remission in people with AAV.

Still, further studies are needed to confirm FCRL5’s predictive potential in GPA and MPA patients, the researchers said.

The study, “Fc receptor-like 5 and anti-CD20 treatment response in granulomatosis with polyangiitis and microscopic polyangiitis,” was published in the journal JCI Insight.

ANCA-associated vasculitis (AAV) is a group of autoimmune diseases caused by the production of autoantibodies — antibodies that wrongly target and attack healthy cells. B-cells, the immune cells responsible for antibody production, are thought to play a key role in AAV development.

Rituximab is approved in the U.S. for treating GPA and MPA, which are two types of AAV. It works by blocking the activity of the CD20 protein found on the surface of certain healthy and malignant B-cells, destroying them.

While originally marketed as Rituxan (by Biogen) in the U.S., Canada, and Japan, and MabThera (by Roche’s subsidiary Genentech) in Europe, other biosimilars of rituximab  — including Truxima and Ruxience — have been approved in recent years.

The therapy has been shown to be effective at inducing disease remission in AAV patients, but previous research indicated that less than half of rituximab-treated patients will still be in full remission after two years.

Therefore, it is crucial to identify biomarkers that can predict treatment responses and help distinguish who will benefit most from these therapies.

A previous study showed that blood levels of FCRL5 before treatment initiation (baseline) predicted responses to rituximab in people with rheumatoid arthritis, also an autoimmune disease. FCRL5 is a protein mainly found on the surface of naïve and memory B-cells, which represent two stages of B-cell development that do not involve active antibody production.

However, whether FCRL5 may be used to predict rituximab responses in AAV patients remains unknown.

To clarify that, researchers at Genentech along with colleagues in the U.S., the U.K., and the Netherlands analyzed baseline blood levels of FCRL5 in 188 GPA and MPA patients who participated in the RAVE Phase 2/3 trial (NCT00104299). That trial showed that rituximab was not inferior to standard therapy at inducing disease remission.

Among these patients, 97 were treated with rituximab and 91 received standard therapy comprised of cyclophosphamide followed by azathioprine (the control group).

In total, 64% of patients in the rituximab group and 54% in the control group achieved complete remission at six months, which was consistent with the response rates observed in the full RAVE patient population (197 individuals).

The team then analyzed whether baseline FCRL5 levels could serve as a predictive biomarker of complete remission with rituximab.

Results showed that in the rituximab group, patients who achieved complete remission at six months had significantly higher mean baseline FCRL5 levels, compared with those who did not.

The patients were classified into two groups — FCRL5-high and FCRL5-low — based on their FCRL5 levels in relation to a threshold found to effectively discriminate rituximab responses at six months. In both treatment groups, about 25% of patients had higher FCRL5 levels at baseline.

Compared with FCRL5-low patients receiving rituximab, those with higher levels showed significantly higher complete remission rates at six months (84% vs. 57%), and later, at 12 months (68% vs. 40%), and 18 months (68% vs. 29%).

Moreover, compared with FCRL5-low patients, a significantly lower proportion of FCRL5-high patients had a GPA diagnosis (65% vs. 81%) and were positive for autoantibodies against proteinase 3 (PR3) (52% vs. 73%). PR3 is one of the most common targets of autoantibodies in AAV.

In the rituximab group, a significantly lower proportion of FCRL5-high patients who achieved complete remission had anti-PR3 autoantibodies (48%), compared with FCRL5-low patients (78%).

Further analysis showed that baseline FCRL5 levels appeared to have a predictive value of rituximab response, regardless of other predictive factors, such as type of vasculitis, presence of relapses, and disease activity.

These findings suggested that patients with high FCRL5 levels at baseline may benefit most from rituximab therapy.

No FCRL5-associated differences were observed in the control group. While both rituximab and the control treatment work to deplete B-cells in the blood, the team found evidence suggesting that differences between rituximab and control groups may be associated with the greater depletion of CD20-positive B-cells seen with rituximab.

“Our analysis is important because it demonstrates that a baseline B-cell marker in GPA and MPA is associated with increased achievement of [complete remission] among patients treated with RTX [rituximab] and may be associated with a prolonged duration of clinical remission following a single cycle of RTX therapy,” the researchers wrote.

The team noted, however, that future studies are needed to confirm these findings.