Reduced glucocorticoid noninferior to high-dose regimen in ANCA-associated vasculitis
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Reduced glucocorticoids alongside rituximab are noninferior to a regimen of high-dose glucocorticoids plus rituximab for remission induction at 6 months in patients with new ANCA-associated vasculitis, according to data published in JAMA.
The findings apply specifically to patients with ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, the authors wrote.
“Two randomized clinical trials, the RAVE and RITUXVAS trials, demonstrated similar remission rates and frequencies of adverse events between rituximab and cyclophosphamide in combination with high-dose glucocorticoids,” Shunsuke Furuta, MD, PhD, of Chiba University Hospital, in Japan, and colleagues wrote. “Data from the two trials suggested that high-dose glucocorticoids are the main contributor to adverse events in the current standard treatment.
“Although previous studies have shown that reducing glucocorticoid dose in combination with conventional immunosuppressants in remission induction was associated with frequent relapses, rituximab has a mechanism of action different from conventional immunosuppressants and retrospective studies have suggested that reduced-dose glucocorticoids plus rituximab could sufficiently induce remission of ANCA-associated vasculitis,” they added.
To examine the efficacy and safety of lower-dose glucocorticoid alongside rituximab (Rituxan; Genentech, Biogen), compared with the conventional high-dose steroid regimen plus rituximab, in inducing remission of ANCA-associated vasculitis, Furuta and colleagues conducted a phase 4, multicenter, open-label, randomized clinical trial. Participants included 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, enrolled between November 2014 and June 2019 across 21 hospitals in Japan.
Half of the participants were randomly assigned to receive 0.5 mg/kg per day of prednisolone, plus weekly 375 mg/m2 doses of rituximab, while the remaining were treated with 1 mg/kg per day of prednisolone alongside the same amount of rituximab. The primary endpoint was remission rate at 6 months, with a prespecified noninferiority margin of –20 percentage points. Safety outcomes included serious adverse events and infections. The follow-up period ended in December 2019.
A total of 134 participants — 69 in the reduced-dose group and 65 in the high-dose arm — completed the trial.
According to the researchers, 71% of participants in the reduced-dose group who completed the trial achieved remission at 6 months, compared with 69.2% of those in the high-dose group. The resulting treatment difference of 1.8 percentage points between the groups met the prespecified criteria for noninferiority (P = .003), they wrote.
Regarding safety, 13 patients in the reduced-dose group, or 18.8%, experienced a total of 21 serious adverse events, compared with 41 serious adverse events across 24 patients in the high-dose arm, or 36.9% (difference = –18.1%; 95% CI, –33% to 3.2%). Meanwhile, there were seven serious infections among five patients in the reduced-dose group, of 7.2%, and 20 serious infections in 13 patients in the high-dose cohort, or 20% (difference = –12.8%; 95% CI, –24.2% to –1.3%).
“In this randomized clinical trial of patients with newly diagnosed ANCA-associated vasculitis, a reduced-dose prednisolone regimen was noninferior to a conventional high-dose prednisolone regimen when combined with rituximab with respect to disease remission rate at 6 months,” Furuta and colleagues wrote. “The reduced dose of prednisolone resulted in significantly reduced serious adverse events including serious infections as well as predefined glucocorticoid-related adverse effects.”
Perspective
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Andrew J. Laster, MD, FACR
Rheumatologists are well-versed in the myriad side effects of corticosteroids so any study that offers further reductions in steroid dosing — without loss of efficacy — for our patient with autoimmune and inflammatory rheumatic diseases should be lauded. In this recently published study in JAMA, Furuta and colleagues demonstrate that “reduced dose” steroid (prednisolone) plus rituximab was noninferior to a “high dose” steroid plus rituximab in treatment of ANCA associated vasculitis. Moreover, there were significantly fewer serious adverse events (SAEs) and serious infections in the “reduced dose” arm.
There were some important limitations. Patients had to have newly-diagnosed disease, the trial was open-label and enrolled individuals residing in Japan, with a relatively small number of subjects (n=70) in each arm. The authors also acknowledge that the basis for setting the noninferior margin by simply duplicating the RAVE trial noninferior margin was “weak”.
Similar to the RAVE trial, those with severe renal disease or pulmonary hemorrhage were excluded. Unlike the RAVE trial where approximately 25% of patients had microscopic polyangiitis (MPO) and 75% granulomatosis with polyangiitis (GPA), far more patients (77-79%) had MPO in the Furuta study and the authors comment that this is typical of ANCA vasculitis seen in Japan.
If we are to incorporate a lower-dose of steroids in our patients with newly-diagnosed ANCA vasculitis, what would that actually look like? The reduced dose employed in the Furuta study and the taper in the RAVE trial have patients off steroids by 6 months; the high-dose arm is still at 10 mg/d. The Furuta reduced dose is clearly a lower dose than what is used in RAVE and has patients at 7.5 mg/d by weeks 5-6, whereas the RAVE trial patient would be at 30 mg. Moreover, RAVE allowed patients to receive 1 gram of methylprednisolone for up to 3 doses before starting prednisone taper.
As a result, the total cumulative dose was greater: A mean of 3595 mg in the RAVE trial vs. median of 1318 in the reduced-dose steroid arm in the Furuta trial. Importantly, the high-dose steroid taper used in the Furuta trial is higher than that used in RAVE. A 70 kg patient would be at approximately 50 mg/d at week 5-6 compared with 30 mg/d in RAVE and at 6 months would still be at 10 mg/d whereas they would be off steroid according to the RAVE protocol if maintained remission.
This also helps to underscore not only the noninferiority when it comes to efficacy of the “reduced dose” steroids in the Furuta trial, but also the significant difference in SAEs when high-dose extended use of steroids are employed for ANCA vasculitis.
As the care of our immunocompromised patients continues to be challenged in the face of the COVID-19 pandemic, patients on rituximab stand out not only for the greater propensity to develop severe disease if infected, but also the potential difficulties in mounting an appropriate immune response to the SARS CoV-2 vaccine. Any attempts to further lower daily steroid dose in these patients will be most welcome.
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