Granulomatosis with polyangiitis (GPA, Wegener’s) and microscopic polyangiitis (MPA) are syndromes of primary systemic vasculitis associated with anti-neutrophil cytoplasm antibodies (ANCA). Together, these syndromes are grouped as ANCA-associated systemic vasculitis (AAV). The prevalence of AAV is 14 to 30 patients per 100,000
. The most common severe AAV manifestations are glomerulonephritis, leading to renal failure and alveolar capillaritis causing lung hemorrhage.
The current standards of care for initial treatment are either combination cyclophosphamide (CYC) and glucocorticoid (GC) therapy or rituximab and GC therapy. Although these treatments have significantly improved survival compared to untreated AAV, overall survival is still poor and many patients suffer from chronic morbidity including end-stage renal disease (ESRD)
Poor survival and ESRD in AAV are attributed both to ineffective therapies and treatment toxicity
. At least 20% of patients do not achieve disease control or are intolerant of initial treatment, and an additional 50% will relapse by 5 years
[4, 5]. Inadequate disease control results in increased immunosuppressive exposure and risk of treatment-related toxicity, progressive organ scarring, and ultimately death
. CYC and GC are also associated with high rates of early mortality due to infection
. Between 25% and 50% of patients with severe AAV experience a severe infection within the first 12 months of treatment and the most frequently cited causes of death are infection or uncontrolled vasculitis
[8, 9]. Strategies that improve disease control and reduce toxicity early in treatment will likely have the largest impact on survival, rates of ESRD, and subsequent disease course. PEXIVAS will evaluate two therapies, one to improve early disease control and one to limit early toxicity.
Plasma exchange (PLEX) was introduced into the treatment of pauci-immune glomerulonephritis following its efficacy in the related anti-glomerular basement membrane (GBM) disease, a disease with renal and pulmonary vasculitis induced by pathogenic anti-GBM antibodies
. The subsequent discovery of ANCA, their close association with GPA and MPA, and animal models supporting the concept of ANCA as pathogenic antibodies, has provided a rationale for PLEX in AAV. Additional potential beneficial effects of PLEX in AAV include removal of other mediators of inflammation and coagulation, and effects on immunoregulation. Furthermore, small trials comparing PLEX to standard treatments suggest benefits for patients with kidney involvement at presentation
[11–13]. Observational work also suggests those with highly active AAV are more likely to benefit from PLEX than those with more chronic presentations
Lung hemorrhage is among the most common vasculitis-related causes of early death in AAV and PLEX is widely used for this presentation. This practice comes from cohort data in AAV and extrapolated experience with anti-GBM disease
[16–18]. However, PLEX has the potential to exacerbate hemorrhage through removal of clotting factors and increases the risk of infection through antibody removal. Furthermore, the observational data most commonly cited focus on non-contemporaneous patients often with severe manifestations of lung hemorrhage
. Contemporary patients are usually diagnosed earlier in their disease course due to the availability of ANCA testing, heightened awareness of the disease, and more routine use of CT scanning, bronchoscopy, and broncho-alveolar lavage.
PLEX is invasive, expensive, labor intensive, and associated with adverse events. There is insufficient high-quality evidence supporting the use of PLEX in AAV, although there are promising data suggesting PLEX may improve survival and prevent ESRD in AAV
[8, 12]; if this is true, PLEX may be a valuable and cost-effective treatment. Due to the uncertainties surrounding the use of PLEX in AAV, there is a need for a randomized controlled trial examining the effect of PLEX on the important clinical outcomes of ESRD and all-cause mortality.
Oral GC are used ubiquitously in the early management of AAV. There is a complex relationship between GC dose and its effects on the immune system as an immunosuppressive versus an anti-inflammatory agent
. When combined with cytotoxic medications, high-dose GC may significantly increase treatment-related toxicity while adding little to therapeutic efficacy. Laboratory data suggest lower GC doses may mitigate their toxicity while maintaining anti-inflammatory effects
. However, there is often a reluctance to reduce GC doses due to their perceived efficacy at higher doses and the association of the disease with poor outcomes when it is not adequately controlled.
Infections in AAV are most common in the first 6 months of treatment when GC doses are highest
. Although this relationship is confounded by disease activity and co-treatment with CYC, it is important to note that infection rates fall in parallel with decreasing GC dose despite the maintenance of constant immunosuppression over time. Replacement of CYC by rituximab has not reduced early infection rates in severe AAV, a finding that supports a major role of GC in infective risk
[9, 21]. The concept that higher doses of GC increase toxicity without improving treatment efficacy in immunologic diseases is supported from evidence in rheumatoid arthritis and lupus nephritis where a dose-dependent increase in infections is observed with increasing GC dose
[22–24]. Furthermore, high cumulative doses of GC are associated with osteoporosis, infections, cardiovascular disease, and gastrointestinal bleeding
. In renal transplantation, concern over GC toxicity prompted early GC withdrawal and even GC avoidance regimens. Meta-analyses of these trials have shown that protocols utilizing more rapid GC withdrawal have not lead to increases in ESRD or death
[25, 26]. Despite the association between higher GC doses and adverse events and despite their widespread use, there is a paucity of literature to guide the optimal use of GC in AAV.
AAV is a rare disease that has ‘orphan’ status in both the US and EU. There are extensive challenges to conducting large, randomized, controlled trials in rare diseases including the need for a large number of study sites to achieve recruitment goals, usually many years for the recruitment period, higher costs per patient compared to studies of common diseases, relative disinterest on the part of the biomedical industry to address clinical problems with small market potential, few drugs with existing indications for a rare disease, and skepticism by funding agencies of the feasibility of such studies
. Conducting adequately powered trials in rare diseases requires establishment of research alliances and ‘buy-in’ by a large number of investigators. Collaborative networks of vasculitis investigators have developed in Europe and North America and have established a track record in completing clinical trials and methodologies for their conduct.
There is a need for therapies for AAV with both reduced toxicity and improved disease control. Defining the role of therapies that are already in use but unproven is a priority for research in AAV. PEXIVAS is a randomized clinical trial testing two interventions in a two-by-two factorial design (standard care and PLEX compared to standard care alone and a standard dose GC compared to a reduced dose GC regimen) to address these issues (ISRCTN # ISRCTN07757494; NCT #NCT00987389).