The presence of detectable ANCA antibodies and B-cells after initial treatment with rituximab — used to induce remission in people with ANCA-associated vasculitis (AAV) — predicts a greater risk of relapse, a new study shows.
The study, “Proteinase-3-anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) predict relapses in ANCA–associated vasculitis patients after rituximab,” was published in Nephrology Dialysis Transplantation.
Rituximab is a medication used both as the first treatment given for a disease, called an induction therapy, and as a maintenance therapy in AAV. Maintenance therapy is follow-up treatment used to help keep a disease from recurring following the initial therapy.
Although it has demonstrated efficacy at inducing remission, previous research has indicated that less than half of individuals treated with Rituximab will still be in full remission after two years.
Finding ways to prevent relapses remains a major goal of clinical research in AAV. Understanding which individuals are most likely to relapse is important in this respect, as it allows for more individually tailored treatment decisions.
“The early detection and prevention of relapses is a key strategy to prevent organ damage and increase survival in AAV patients,” the researchers wrote.
Rituximab works by killing the immune B-cells responsible for producing antibodies. In AAV patients, a set of antibodies called ANCAs — a key protein factor in the blood — are the main cause of the blood vessel damage that marks the disease. These antibodies most commonly target either the myeloperoxidase (MPO) or the proteinase 3 (PR3) proteins.
Previous studies have suggested that ANCAs and B-cells could be predictive of AAV relapses following rituximab treatment. However, the utility of these markers has been debated, in large part because relapses have been documented in individuals without detectable ANCAs or B-cells.
In the new study, the researchers analyzed data for 110 ANCA-positive AAV patients who were treated at the Leiden University Medical Center in the Netherlands between January 2006 and 2018. All received rituximab to induce remission, followed by maintenance therapy with rituximab or other standard treatments.
Among the patients, 77% had granulomatosis with polyangiitis (GPA), and 23% had microscopic polyangiitis (MPA). Their average age was 60 years, and most were male (61%) and positive for ANCAs against PR3 (80%).
All patients were followed for at least two years after the initial induction treatment. In that time, 31 experienced relapses. The researchers examined relapse frequency based on ANCAs, B-cells, and a combination of both.
For ANCAs, the patients were divided into three groups: those consistently positive for ANCAs following treatment — that is, they continued to have detectable levels of these antibodies — those consistently negative for ANCAs following induction therapy, and those who were initially negative, but later positive (reappearance).
The relapse rates were significantly lower among those who were persistently negative for PR3-ANCA following treatment (3%), compared with those who were persistently positive (37%) or had PR3-ANCA reappearance (50%).
Among MPO-ANCA-positive patients, all relapses occurred in individuals who were persistently positive (41%). There were no relapses in individuals who were persistently negative or had reappearance (0%).
Following induction treatment, 87% of patients with available data had full depletion of B-cells, meaning they had no detectable B-cells after rituximab treatment. The subsequent repopulation of B-cells was observed in 68% of the patients.
Depletion rates were not significantly different among those with various ANCA types, but repopulation was significantly more common among MPO-ANCA-positive patients (75%) as compared with those who were PR3-ANCA-positive (67%).
The patients with full B-cell depletion had a significantly lower relapse rate (27%) than those without (60%). Similarly, individuals who remained B-cell-depleted had a significantly lower relapse rate (15%) than those who experienced repopulation (41%).
When the two predictor types were combined, patients who remained positive for PR3-ANCA after induction therapy were at increased relapse risk, regardless of their B-cell status. Among MPO-ANCA-positive patients, only those who experienced B-cell repopulation had recorded relapses (58% vs. 0% for those without repopulation).
“Persistent or the reappearance of PR3-ANCA positivity predicted almost all relapses, while relapses in MPO-ANCA-positive patients were all restricted to patients with persistent MPO positivity and B-cell repopulation,” the researchers wrote.
“Based on our study, a tailored ANCA/B-cell-guided [rituximab] approach can be envisioned that should be evaluated in prospective studies to establish whether ANCA and B-cell immunomonitoring actually reduce overtreatment and damage accrual in AAV patients,” they concluded.