Rituxan Plus Lower Prednisolone Effective With Fewer Side Effects

Using lower doses of prednisolone in combination with Rituxan (rituximab) resulted in similar rates of remission and fewer adverse events than Rituxan plus higher doses of the glucocorticoid in treating ANCA-associated vasculitis (AAV).

Those were the findings of a Phase 4 clinical trial in Japan that examined the effects of high-dose glucocorticoids — which are linked to side effects such as osteoporosis, peptic ulcers, skeletal muscle disorders known as myopathy, and cataracts — versus lower doses when used as an add-on therapy to Rituxan for people newly diagnosed with AAV.

“To our knowledge, this is the first trial in ANCA-associated vasculitis showing that a lower glucocorticoid dose may reduce serious adverse events,” the researchers wrote, noting that such side effects “significantly decrease patients’ quality of life.”

Together with the results of other recent studies, these findings suggest that “the total dose of glucocorticoids during the remission induction phase could be reduced in most patients with ANCA-associated vasculitis when combined with appropriate, potent treatment,” the researchers wrote.

The study, “Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis — A Randomized Clinical Trial,” was published in the journal JAMA.

AAV is a group of diseases caused by the immune system mistakenly attacking small blood vessels, leading to inflammation and damage to organs, primarily the kidneys and lungs.

The current standard therapy for newly diagnosed patients combines high-dose immune-suppressing glucocorticoids and either cyclophosphamide or Rituxan. Although these treatments have high remission rates, they are associated with substantial adverse events, which are thought to be due to the elevated doses of glucocorticoids. Those adverse effects, which include the bone disease osteoporosis, stomach ulcers, muscle weakness, and blurred vision due to cataracts, can severely and negatively affect the quality of life of people with AAV.

According to the researchers, previous studies have shown that reducing glucocorticoid doses in combination with conventional immunosuppressants is associated with frequent disease relapses. However, Rituxan has a different mechanism of action than these conventional immunosuppressants. It works, the scientists noted, by reducing the number of ANCA-producing immune B-cells that are present at inflammation sites and which correlate with disease activity.

Thus, an examination of patients’ medical records suggested that disease remission could be achieved with Rituxan even when used in combination with lower glucocorticoid doses.

To test this theory, the team — from several different hospitals and universities across Japan — designed a Phase 4 clinical trial (NCT02198248). The trial compared the safety and efficacy of reduced dose glucocorticoid plus Rituxan with the standard high-dose glucocorticoid plus Rituxan regimen in newly diagnosed AAV patients.

A Phase 4 trial is one that is conducted after a treatment has been approved.

In this open-label study, a total of 140 patients — none of whom had severe kidney or lung damage — were randomly assigned to receive Rituxan with either high-dose (1 mg/kg, each day) or low-dose (0.5 mg/kg per day) prednisolone.

In the reduced-dose group, prednisolone was stopped at five months, whereas the dose of prednisolone was lowered to a total of 10 mg/day by five months in the high-dose group.

The median age was 74 among the patients in the high-dose prednisolone group, and 62.3% were women. In the reduced-dose group, the median age was 73, and 56.9% were women.

The study’s main goal was to determine if the low-dose treatment was at least as effective as the standard high-dose approach at inducing remission at six months — defined score of 0, or no activity, on the Birmingham Vasculitis Activity Score (BVAS), a measure of disease activity.

Additional measures included the proportion of patients who died, those who relapsed, and patients who experienced kidney failure. The proportion of individuals with serious adverse events also was examined.

The analysis revealed that, at six months, 71% of participants in the reduced-dose group achieved remission, compared with 69.2% in the high-dose group. This 1.8% difference was considered significantly similar or non-inferior. Furthermore, these results remained after adjusting for ANCA subtype, age, and kidney function.

There also were no significant differences between the two groups in the analysis, at six months, of other secondary efficacy outcomes, namely the scores on the BVAS and Vasculitis Damage Index, which assesses disease and treatment damage.

The groups also had similar death rates at six months (2.9% vs. 4.6%), and a similar proportion of patients with kidney failure (0% vs. 1.5%).

Although a patient-reported visual analog scale for disease activity was the same for both groups, treatment toxicity at six months, also assessed by the participants, was lower in the reduced-dose group than in the high-dose group. Quality of life measures for both physical and mental outcomes also showed no differences between groups.

Regarding safety, a total of 13 participants (18.8%) in the low-dose group reported 21 serious adverse events, whereas 41 adverse events occurred in 24 patients in the high-dose group (36.9%). Serious infections also were less frequent in the reduced-dose group, with seven infections appearing in five participants. In the high-dose group, 20 infections were reported in 13 patients.

Predefined glucocorticoid-related adverse events also were less frequent in the reduced-dose group than in the high-dose group. These included diabetes, which was reduced by 20.8%, insomnia, which was decreased by 16.2%, and all infections, which were lowered by 28.7%.

Median levels of C-reactive protein in the bloodstream — a marker for inflammation — were not significantly different between the groups, and nor were median eGFR values, a measure of kidney function. The levels of antibodies, required to fight off infections, fell after the start of treatment in both groups but were higher in the reduced-dose group at six months.

“Among patients with newly diagnosed ANCA-associated vasculitis without severe [lung and kidney damage], a reduced-dose glucocorticoid plus rituximab regimen was non-inferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months,” the investigators concluded.