Landmark Trials in ANCA-Associated Vasculitis: Past, Present and To Be Cont’d…

Posted on RFN: March 22, 2019

Updated: November 2020

Anti-neutrophil cytoplasm antibody (ANCA) was first described in 1982 in a case of segmental necrotizing glomerulonephritis (Fig. 1). The first international ANCA workshop in 1989 delineated a standard immunofluorescence technique to test for ANCA in kidney biopsy specimen. During the second international ANCA workshop, the term “peri-nuclear ANCA” (p-ANCA) was accepted and soon after, ANCA serum antibodies assay were used as a diagnostic tool in ANCA glomerulonephritis.

ANCA-associated vasculitis (AAV) is now defined as a pauci-immune necrotizing vasculitis of predominantly small blood vessels that is associated with myeloperoxidase (MPO-ANCA), proteinase 3 (PR3-ANCA) positivity.

In this post, we’ll review the data that guide our treatment of AAV.

Let’s start with cyclophosphamide:
Starting in the 1970s, cyclophosphamide (CYC) and glucocorticoids were found to be effective in ANCA vasculitis. Two decades later in 1992, a study of 158 patients with granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) summarized that the outcome could be dramatically improved by daily treatment with cyclophosphamide and glucocorticoids, though disease-related and treatment-related morbidity were often profound, 13% of patients died, 86% of patients had irreversible features of their disease and 42% of patients had side effects of treatment.

In 2009, the CYCLOPS trial compared the effectiveness of oral versus intravenous (IV) CYC induction. When oral and IV CYC were compared, neither was more likely to induce remission or got there faster The IV group did have a lower rate of leukopenia and infection, however, it is important to mention that the oral cyclophosphamide group had a higher cumulative steroid dose when compared to the IV group (16 vs 8g). The study was not powered to look at relapse rates initially, but long-term follow up of the cohort showed higher relapse rates in the IV group, presumably related to the higher cumulative CYC dose in the oral group. There was no differences in renal or overall survival.

Now onto glucocorticoids…

For active AAV, current treatment guidelines suggest glucocorticoids beginning at high doses followed by a steroid taper. Patients with AAV with rapidly progressive GN or alveolar hemorrhage typically receive pulse methylprednisolone, 500 to 1,000 mg, daily for 3 days. There is no consensus for tapering strategies. PEXIVAS, a recent large multicenter study of severe AAV assigned 704 patients in a 2 × 2 factorial design to plasma exchange or none and to standard-dose or low-dose glucocorticoid treatment (cumulative dose ∼50% of standard group) on a background of cyclophosphamide or rituximab induction. There was no difference in efficacy between the 2 glucocorticoid groups, but a reduction in severe infections was seen in the first year in the low-dose glucocorticoid group. They concluded that a reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD.

What about rituximab (RTX)?
The RAVE trial, in which patients with both new and relapsing GPA/MPA were enrolled, compared RTX and CYC for induction, with each treatment given in addition to glucocorticoids. The trial showed that glucocorticoids plus RTX were not inferior to CYC for the treatment of new onset AAV. Moreover, this regimen was found to be superior in relapsing AAV. Notably, in the RAVE trial, sicker patients including those with alveolar hemorrhage requiring mechanical ventilation or severe kidney failure with creatinine greater than 4.0 mg/dL were excluded. Subsequently, the RITUXIVAS trial recruited only patients with newly diagnosed GPA/MPA with more severe kidney disease, including patients requiring dialysis showed similar data to the RAVE trial, demonstrating rituximab was noninferior to cyclophosphamide for remission induction, with comparable rates of adverse events.. Notably in the RITUXIVAS trial, IV CYC was given with the first and third RTX infusions and plasmapheresis was allowed.

In April 2011, rituximab was approved by the US Food and Drug Administration as an alternative to cyclophosphamide in combination with glucocorticoids for treatment of severe GPA/MPA. Rituximab is now the preferred treatment for patients with relapsing disease, refractory disease, and those with contraindications to cyclophosphamide. Infact in a subgroup analysis, the RAVE trial demonstrated that rituximab was superior to cyclophosphamide for remission induction in patients with PR3-positive ANCA.

Should we do plasmapheresis?
The role of plasmapheresis has been a recent area of debate in terms of hard outcome benefits. The first randomized study published in 1991 concluded that plasma exchange provided additional benefit to dialysis-dependent patients. However, the difference was less pronounced during a 12-month follow-up period. Similarly, in 2007, the MEPEX study showed reduction in risk of progression to ESRD in patients with serum creatinine >5.7 mg/dL, but again, longer term follow up showed that the difference disappeared after 12 months for ESKD and mortality. The PEXIVAS trial evaluated the role of plasma exchange in patients with severe AAV. By contrast, this study showed no difference in primary end points of incidence of death or ESKD between the plasma exchange or no plasma exchange groups, and subgroup analysis failed to show a benefit in patients with pulmonary hemorrhage.

Will we have any complement inhibitors in the future?

Yes! Well maybe. With encouraging data from phase 2 studies, a multicenter phase 3 trial of avacopan in AAV has completed enrollment, and the results are eagerly awaited ADVOCATE.

Finally, maintenance therapy.
It has been established that induction therapy will need to be followed by maintenance treatment. The CYCAZAREM trial in 2003 showed CYC could be safely transitioned to azathioprine (AZA) for maintenance. The IMPROVE trial in 2010 higher rates of relapse in patients treated with MMF compared to than AZA.

There is a role for rituximab for remission maintenance. The MAINRITSAN trial in 2014 superiority of rituximab, in maintaining remission when compared to the azathioprine arm even at 60 months!.. The MAINRITSAN 2 trial compared fixed-dose rituximab dosing with rituximab dosing tailored to B-cell reappearance (CD19 count > 0) and ANCA titers (reappearance or doubling). At 28 months, there was no difference in relapse or adverse events between the 2 groups, but the number of infusions was reduced in the tailored group.

Remember all the above maintenance trials used cyclophosphamide for the control arm and did not compare it to AZA.

RITAZEREM trial addresses this pitfall by comparing rituximab with AZA in patients with relapsing AAV who received rituximab for induction. Their results suggest following induction of remission with rituximab, rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. There were no new major safety signals for use of these medications in this population (ACR plenary presentation etc). However, we await the full publication of the results from this trial!

Well don’t we have options for maintenance therapy! How long should we continue these for again? The REMAIN trial(2017) is a randomized controlled trial that tested whether continuing azathioprine and prednisone treatment for 48 months was more effective in relapse prevention than withdrawal at 24 months. Results from this study showed a significant decrease in relapses and better renal survival in the continuation group. But the relapses in the withdrawal were few indicating that >60% of individuals may not need prolonged therapy. We don’t have any trials assessing the duration of rituximab maintenance therapy.

Looking back on the history of AAV treatment, it is exciting to see how the knowledge of AAV treatment has evolved and drastically changed AAV from a disease with 80% mortality to a chronic relapsing-remitting disease. Nevertheless, the optimal regimen of induction and maintenance treatment has evolved but we still have a few miles to go.

Post By: Natanong Thamcharoen, MD and Danwen Yang, MD

Edited by: Rhea Bhargava, MD.