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Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) refers to a group of vasculitides that mainly affect small vessels and are pauci-immune in nature. In particular, granulomatosis with polyangiitis (GPA) is associated with significant morbidity and mortality, primarily from disease affecting the kidneys and lungs.

Renal disease, in the form of rapidly progressive glomerulonephritis, can lead to end-stage renal disease (ESRD) requiring hemodialysis. A recent of the United States Renal Data System of patients with ESRD due to GPA found that, from 1995-2014, overall mortality had declined. Despite the improvement, there was still a significant mortality rate of 25% at 2-year follow-up for patients enrolled during the period of 2010-2014. Therapy that can reduce renal damage in GPA would theoretically improve survival.

One such example, plasma exchange (PLEX), has been utilized for this purpose, with some small that have suggested benefit. However, validation with a large study has been pending.

Diffuse alveolar lung hemorrhage is one of the most common causes of early death in AAV and PLEX has been widely used to treat patients that have this presentation. According to a , of St. Joseph's Hospital in London, Ontario, Canada, and colleagues, the practice was derived from experience of PLEX in anti-glomerular basement membrane (GBM) disease.

However, PLEX is not without risk of adverse effects. In fact, as mentioned in the 2013 article on PEXIVAS, hemorrhage can be worsened due to the removal of clotting factors. Infection risk can also increase due to antibody removal. This risk is not negligible when considered that in the early course of AAV disease, concurrent use of standard high dose glucocorticoids already places the patient at high risk for serious infections. Unfortunately, infections remain one of the most frequently cited causes of death in patients with AAV, as seen in studies from and .

At the American College of Rheumatology (ACR) annual meeting at Chicago, the were presented by Peter A. Merkel, MD, MPH, of the University of Pennsylvania in Philadelphia. The trial results answered the questions of whether PLEX improves outcomes in AAV, and also if a lower-dose glucocorticoid regimen would increase the risk of ESRD or death.

Patients with new or relapsing severe AAV, with symptoms such as lung hemorrhage and/or glomerulonephritis (eGFR <50 ml/min/1.73 m²) were included in the study. The 704 participants were from 98 sites in 15 countries, making it the largest trial in AAV to date. The trial was a 2-by-2 factorial, randomized, controlled trial evaluating plasma exchange outcomes and two different regimens of oral glucocorticoids simultaneously.

Patients were randomized to receive either no plasma exchange or seven treatments of PLEX. Patients were also randomized to receive a standard dose of oral glucocorticoid regimen or a reduced-dose (<60% of the standard regimen by 6 months). All received immunosuppression via cyclophosphamide or rituximab (Rituxan) plus IV methylprednisolone. Patients were then followed for up to 7 years for the primary composite outcome of death or ESRD.

Among the patients, death or ESRD occurred in 28% of patients allocated to PLEX compared with 31% in the no plasma exchange group, indicating no improvement in the outcome of patients who received PLEX. The primary outcome occurred in 28% of patients in the reduced glucocorticoid group and 26% in the standard glucocorticoid group.

The use of reduced glucocorticoid doses produced non-inferior results. However, the patients who received reduced glucocorticoid doses had a significant reduction in serious infections in the first year. These results gave physicians some food for thought into the current management paradigm of patients with AAV.

In consideration of the PEXIVAS results, the high cost, as well as the invasive nature of PLEX, it is unknown what role PLEX will still serve for patients with renal involvement related to AAV.

"This is the largest clinical trial ever done in the field of vasculitis, and I believe that both findings of lack of effectiveness for PLEX and the efficacy of a reduced steroid approach should be practice changing," said , co-director of the Center for Vasculitis Care and Research and head of the section of Clinical Immunology at the Cleveland Clinic.

Most importantly, the PEXIVAS data provides reassurance that if a patient cannot tolerate the standard high dose glucocorticoids and has to receive a reduced dose, there is no perceived increased risk in future mortality or development of ESRD. This is important since more guidance for the usage of glucocorticoids in AAV is still needed.

PEXIVAS is an impressive study for the sheer magnitude of its sample size in such rare diseases as AAV. In addition, its efforts to further define the role of established therapies, such as PLEX and standard high dose glucocorticoid use in the management of AAV, allow physicians to re-evaluate their risks and true benefit in the treatment decision-making process.

Anny Wu, DO, completed her internal medicine residency at McLaren Greater Lansing in Lansing, Michigan. She is currently a second-year rheumatology fellow at Franciscan Alliance in Munster, Indiana, and has special interests in vasculitis and autoimmune myositis.