Low-dose glucocorticoids just as effective for long-term AAV control

Risk of serious side effects significantly reduced with lower dosage regimen

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An illustration of a clinical trial is framed by medicines and a stethoscope.

A treatment regimen that combines low-dose glucocorticoids and rituximab is just as effective at controlling ANCA-associated vasculitis (AAV) as a standard regimen of high-dose glucocorticoids and rituximab, according to two-year data from a clinical trial.

The long-term findings indicate that, while the efficacy is comparable, the risk of serious side effects is significantly reduced with the low-dose regimen, supporting it as a strategy.

The study, “Reduced-dose versus high-dose glucocorticoids added to rituximab on remission induction in ANCA-associated vasculitis: predefined 2-year follow-up study,” was published in the Annals of the Rheumatic Diseases.

AAV is marked by self-reactive antibodies, called ANCAs, being produced that cause inflammation in small blood vessels, damaging the kidneys and lungs.

Standard AAV treatment generally combines high-dose glucocorticoids, due to their rapid and potent anti-inflammatory and immunosuppressive effects, along with immunosuppressives, such as rituximab or cyclophosphamide.

Given that long-term treatment and higher doses of glucocorticoids are associated with severe side effects, “reduced-dose glucocorticoid or glucocorticoid-free regimens have recently been evaluated in clinical trials,” wrote researchers in Japan who launched a Phase 4 clinical trial called LoVAS (NCT02198248) wherein people with AAV without serious lung or kidney disease were treated with rituximab plus prednisolone at either 1 mg/kg/day or 0.5 mg/kg/day.

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Low-dose vs. high-dose glucocorticoids for AAV

After five months, prednisolone was discontinued in the reduced-dose group, and reduced to 10 mg/day in the high-dose group. Maintenance treatment with rituximab was maintained for up to two years.

Sold under the name Rituxan and MabThera, and with biosimilars available, rituximab works by killing antibody-producing B-cells.

The study’s main goal was to compare how well the two regimens could induce remission at six months. Top-line data previously showed comparable effectiveness between them, with roughly 70% of patients in either group achieving it. Serious side effects were less frequent in the low-dose group (18.8% vs. 36.9%).

The long-term effects of the low-dose regimen weren’t known, however, leading the researchers to analyze two-year data from LoVAS to compare outcomes between the two. The analysis included data from 69 patients given the low-dose regimen and 65 given the standard regimen.

Relapse rates were slightly higher in the standard regimen group (13% vs. 7.6%), but group differences didn’t reach statistical significance, meaning these were likely due to chance. Similar results were obtained when the team looked only at the subset who achieved remission at six months.

No significant group differences were found for measures of patient-reported disease activity and quality of life at two years, as well as mortality rates, with two deaths reported in the low-dose group (2.8%) and five in the high-dose group (7.6%). One case of kidney failure occurred in the high-dose group. None was reported in the low-dose group.

“Relapse rates at 24 months were not significantly different between the treatment groups, and other efficacy outcomes were not also different between the groups,” the researchers wrote.

Among those who’d achieved remission at six months, 89.7% in the low-dose group were no longer taking glucocorticoids at two years compared with only 15.5% in the standard dose group. This suggests that “once the disease remission is achieved, long-term administration of glucocorticoids might not be necessary for patients treated with the rituximab maintenance therapy.”

Prevalence of serious side effects

Serious side effects were significantly less common in the low-dose group relative to the high-dose group (27.5% vs. 46.2%), as were serious infections (10.1% vs. 24.6%). Other common glucocorticoid-related side effects, including nonserious infections, insomnia, and broken bones, occurred at a significantly lower frequency in the low-dose group. The difference was particularly striking in the first months of treatment when the risk of serious side effects is highest, the researchers said.

The percentage of patients who saw a composite outcome of death, relapse, kidney failure, and serious adverse events was comparable between the lower dose and standard regimen (36.2% vs. 49.2%), as was the cumulative survival rates without such events (62.7% vs. 51.2%).

The findings underscore that “from a short-term and a long-term viewpoint, the benefit of the reduced-dose regimen was confirmed,” the scientists wrote, noting, however, the trial was mainly designed to compare differences after six months and the sample size might not have been large enough to detect significant group differences in terms of outcomes. They also noted the results may not be applicable to all patients, given that all the participants in this trial were Japanese and most were positive for antibodies against myeloperoxidase, one of the two most common targets of ANCAs.