Update on the management of ANCA-associated vasculitis

Jan. 11, 2019

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis comprises three different syndromes — granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis); microscopic polyangiitis (MPA); and eosinophilic granulomatosis with polyangiitis (EGPA, also known as Churg-Strauss syndrome) — all with frequent respiratory manifestations.

Diffuse alveolar hemorrhage (DAH) caused by capillaritis occurs in about 25 percent of patients with GPA and MPA, either at presentation or during a disease relapse, whereas DAH is extremely rare in EGPA. Patients with DAH usually have detectable ANCAs, either targeting proteinase 3 (PR3) or myeloperoxidase (MPO). Lung nodules, masses or cavities are disease-defining consequences of necrotizing granulomatous inflammation in GPA. Tracheobronchial involvement also is a feature predominantly of GPA, rarely found in MPA but not in EGPA. Asthma and eosinophilic pneumonia are disease-defining features of EGPA when they occur in patients with features of small vessel vasculitis.

Cyclophosphamide and rituximab

Recent studies have shown that ANCA specificity (PR3 versus MPO) is more important for prognosis, relapse risk, response to therapy and outcomes than the specific diagnosis (GPA versus MPA). Specifically, the presence of PR3-ANCA (rather than MPO-ANCA) portends a better response to rituximab than to cyclophosphamide, but also a much higher relapse risk, and hence the need for ongoing maintenance therapy. For patients with EGPA, the presence of ANCA (usually MPO-ANCA) conveys a vasculitic disease phenotype, and glomerulonephritis or DAH is very unusual in the absence of ANCA.

For management purposes, GPA and MPA are considered together because of significant clinical overlap at presentation and similar treatment response. By contrast, asthma and specific disease manifestations caused by eosinophilic inflammation define the treatment needs of patients with EGPA.

Rituximab has been found superior to cyclophosphamide for patients positive for PR3-ANCA and for patients with relapsing GPA or MPA and therefore has essentially replaced the use of cyclophosphamide. This outcome is also true for patients with DAH requiring mechanical ventilation, as confirmed in research published in Arthritis & Rheumatology in 2016.

For patients with MPA or MPO-ANCA-associated vasculitis, cyclophosphamide remains an option for remission induction because these patients respond equally well to cyclophosphamide or rituximab, and they have a much lower relapse risk than those with PR3-ANCA or GPA. However, for patients with MPA or MPO-ANCA-associated vasculitis who experience a disease relapse, or for whom fertility preservation or compliance is of concern, rituximab is preferable to cyclophosphamide.

Rituximab is also emerging as an effective and safe remission maintenance agent. A randomized controlled trial has documented that rituximab given at a dose of 500 mg intravenously every six months following remission induction with glucocorticoids and cyclophosphamide in newly diagnosed patients is superior to daily oral azathioprine for maintenance of remission.

This trial also showed rituximab to be cost-effective because higher drug costs were offset by increased cost of care arising from relapses and subsequent end-stage renal disease occurring at a higher frequency when azathioprine was used for remission maintenance. Trial results were published in the New England Journal of Medicine in 2014.

Prompted by a better understanding of the short-term and long-term risks associated with glucocorticoid use, the focus of clinical research in ANCA-associated vasculitis has shifted toward minimizing glucocorticoid use. To date, high-dose glucocorticoids remain necessary for remission induction, regardless of whether rituximab or cyclophosphamide is used. Yet the improvements in overall outcomes have not substantially altered the early (within three to six months after diagnosis) mortality of about 10 percent, more than half of which is related to sepsis and other severe infections. Uncontrolled underlying vasculitis disease activity accounts for less than 20 percent. Therefore, new drugs that can safely control the acute inflammatory response of the innate immune system as well as glucocorticoids are under investigation.

A double-blind, double-placebo-controlled, multicenter phase III trial in 300 patients with GPA or MPA has recently completed enrollment. In this trial, a small molecule (oral agent) inhibitor of the receptor for activated complement factor 5, avacopan, is being compared head-to-head with standard glucocorticoid dosing for remission induction. Results of this trial will be available next year.

Another landmark randomized controlled trial conducted in 700 patients with GPA or MPA was designed to evaluate the efficacy of adjunct plasma exchange and to compare standard glucocorticoid dosing with an accelerated glucocorticoid tapering regimen. Headline results of this trial were presented in June 2018 as showing no efficacy of plasma exchange in the entire cohort or any clinical subset (severe renal disease or DAH), while the accelerated glucocorticoid tapering regimen was as effective but safer (lower infection rate) than the standard glucocorticoid dosing.

Reducing the cumulative glucocorticoid dosing is also a major issue in EGPA, as patients often require significant ongoing use of systemic glucocorticoids to control severe asthma, rhinosinusitis and nasal polyposis, long after the vasculitic disease manifestations have been well-controlled.

The recently completed randomized, placebo-controlled, phase III trial of mepolizumab (300 mg subcutaneously once a month) has shown superiority to the standard of care for all primary and secondary endpoints of the trial, leading to FDA approval of mepolizumab for use in EGPA, and its availability as a welcome option for patients who cannot sustainably reduce their systemic glucocorticoid usage below a level of about 7.5 mg of prednisone daily. Trial results were published in the New England Journal of Medicine in 2017.

For more information

Cartin-Ceba R, et al. Diffuse alveolar hemorrhage secondary to antineutrophil cytoplasmic antibody-associated vasculitis: Predictors of respiratory failure and clinical outcomes. Arthritis & Rheumatology. 2016;68:1467.

Guillevin L, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. New England Journal of Medicine. 2014;371:1771.

Longitudinal Protocol for Granulomatosis With Polyangiitis (Wegener's) and Microscopic Polyangiitis. Mayo Clinic.

Wechsler ME, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. New England Journal of Medicine. 2017;376:1921.