Plasma exchange did not decrease the incidence of death or progression to end-stage kidney disease (ESKD) among patients with severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis complicated by renal dysfunction or pulmonary hemorrhage, a multinational randomized clinical trial found.
In a study known as PEXIVAS that included 704 patients followed for a median of 2.9 years, the combined primary endpoint of death or ESKD occurred in 28.4% of patients given plasma exchange along with conventional immunosuppressive therapy and in 31% of those not given plasma exchange, which was not a significant difference (HR 0.86, 95% CI 0.65-1.13, P=0.27), reported Michael Walsh, MD, PhD, of the Population Health Research Institute of McMaster University-Hamilton Health Sciences in Ontario, and colleagues.
The study also considered whether lowering the dose of glucocorticoids — a mainstay of treatment but one that is associated with serious adverse events when given in high doses over long periods — could be as effective as standard doses. The results, published online in the New England Journal of Medicine, demonstrated that death or ESKD occurred in 27.9% of patients given a reduced-dose regimen and 25.5% of those on standard doses, for an absolute risk difference of 2.3 percentage points (90% CI -3.4 to 8).
Accordingly, with a noninferiority margin of 11 points, the reduced-dose regimen was considered noninferior to the standard-dose regimen, the team noted.
“I think the PEXIVAS trial will lead to substantial change in practice and standard of care for ANCA-associated vasculitis,” said Peter A. Merkel, MD, chief of rheumatology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia and one of the trial’s three principal investigators.
“Certainly it will change glucocorticoid dosing for induction and remission,” he told MedPage Today.
The Disease and the Trial
ANCA-associated vasculitis involves inflammation of the small and medium-sized blood vessels, with the kidney being particularly vulnerable, and patients with the disease continue to have high rates of ESKD and early death. “Poor outcomes are attributed to a delay in diagnosis and to the use of treatments that have a slow onset of action, incomplete efficacy, and toxic effects. More effective, safer therapies are needed,” Walsh and colleagues wrote.
Previous studies have demonstrated considerable benefits with plasma exchange to remove pathogenic ANCAs among patients with severe renal vasculitis, and international guidelines favor the use of this treatment for ANCA-associated vasculitis with pulmonary hemorrhage. However, efficacy has never been proven.
High-dose glucocorticoids were the first effective treatment for ANCA-associated vasculitis, and continue to be widely used. However, the current trend in autoimmune disease has been toward steroid-sparing treatments.
Therefore, to explore the possibility that treatment efficacy and safety could be improved with plasma exchange and/or lowering glucocorticoid doses, Walsh and colleagues enrolled patients during 2010 to 2016 from 95 centers in 16 countries. This was the largest trial ever done for ANCA-associated vasculitis, the researchers noted.
All patients were given induction treatment with intravenous or oral cyclophosphamide or rituximab (Rituxan). Participants were also given intravenous methylprednisolone for the first 1 to 3 days, followed by oral prednisone or prednisolone on a weight-based basis.
For the first week, the standard-dose and reduced-dose groups received the same treatment, and thereafter the dose was halved in the reduced-dose group. By month 6, the cumulative dose in the reduced-dose group was less than 60% of the cumulative dose in the standard-dose group.
For those randomized to plasma exchange, the treatment was given seven times over 14 days.
Patients’ mean age was 63, and the majority were men. Median serum creatinine level was 330 µmol/L, and median C-reactive protein level was 46 mg/L.
Pulmonary hemorrhage was present in 191 patients, and was severe in 61.
For the plasma exchange analysis, no differences were seen on any secondary outcomes. The hazard ratios were 0.87 (95% CI 0.58-1.29) for death from any cause and 0.81 (95% CI 0.57-1.13) for ESKD, while the relative risk for sustained remission was 1.01 (95% CI 0.89-1.15). The incidence rate ratios were 1.21 (95% CI 0.96-1.52) for serious adverse events and 1.16 (95% CI 0.87-1.56) for serious infections at 1 year.
On the reduced-dose versus standard-dose glucocorticoid analysis, a significantly lower risk of serious infections in the first year was seen in the reduced-dose group, with an incidence rate ratio of 0.69 (95% CI 0.52-0.93). Nonsignificant hazard ratios of 0.78 (95% CI 0.53-1.17) were seen for death from any cause and 0.96 (95% CI 0.68-1.34) for ESKD, relative risk for sustained remission was 1.04 (95% CI 0.92-1.19), and the incidence rate ratio was 0.95 (95% CI 0.75-1.20) for serious adverse events.
“Showing, within the limits of precision that we could estimate, that the reduced-dose regimen decreased the risk of serious infections without increasing the risk of other adverse events represents an important step toward standardizing care,” the investigators wrote.
A limitation of the study, they said, was its open-label design.
Implications for Practice
“I think this study also will likely substantially reduce the use of plasma exchange for this disease,” said Merkel.
“But I’m not sure it will eliminate its use for certain situations and some patients. Even though this was the largest study ever done in ANCA-associated vasculitis, there may be individual subsets and clinical situations where people feel it’s appropriate,” he added.
That was highlighted in an accompanying editorial by Vimal K. Derebail, MD, and Ronald J. Falk, MD, both of the University of North Carolina at Chapel Hill. They pointed out that a subgroup analysis suggested a possible benefit on the primary combined outcome in patients with pulmonary hemorrhage. For those with nonsevere pulmonary hemorrhage, the hazard ratio for death or ESKD was 0.64 (95% CI 0.33-1.24) and for those with severe hemorrhage, the hazard ratio was 0.67 (95% CI 0.28-1.64).
“In our judgment, until a study specifically designed to evaluate efficacy in patients with pulmonary hemorrhage has been performed, plasma exchange should remain part of the induction regimen for patients with ANCA-induced pulmonary hemorrhage,” Derebail and Falk wrote.
That recommendation was in contrast to the observation by the PEXIVAS investigators, who stated: “The results do not support a treatment effect in patients with pulmonary hemorrhage that differs from that in patients without pulmonary hemorrhage.”
Derebail and Falk also suggested that plasma exchange might be considered for certain other subgroups of patients, such as those with anti-glomerular basement membrane disease.
With regard to the study itself, Merkel concluded: “This was a tremendous international collaboration. We dealt with people from multiple countries for many years, and it’s a testament to the collaborative nature of the vasculitis research community.”
The study was supported by the National Institute for Health Research U.K., the Food and Drug Administration, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institutes of Health, the National Health and Medical Research Council, Australia, the Canadian Institutes of Health Research, the French Ministry of Health, the Research Committee on Intractable Vasculitides of the Ministry of Health, Labor, and Welfare of Japan, and the Japan Agency for Medical Research and Development.
Plasma exchange materials were provided by Terumo, Fresenius Medical Care Australia, Baxter Healthcare, and Asahi Kasei Medical.
The authors reported financial relationships with AbbVie, Biogen, CSI, Behring, Genzyme, Insmed, Janssen, Kiniska, Sparrow, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, Genentech/Roche, GlaxoSmithKline, InflaRx, Kypha, Pfizer, LFB, Sanofi, Amgen, Shire, Fresenius, Retrophin, Calliditas, and Eli Lilly.