Pauci-immune small vessel vasculitis characterizes a necrotizing group of vasculitides with potential multi-organ and life-threatening disease that is typified by the scarcity of immune complex deposits in vessel walls on histology. Central to its known pathogenesis is the activation of primed neutrophils through the interaction of circulating anti-neutrophil cytoplasmic autoantibodies (ANCA) with myeloperoxidase (MPO) and proteinase-3 (PR3) target autoantigens expressed on their cell surface [[1], [2], [3], [4]]. Therefore, the term ANCA associated vasculitis (AAV) is commonly used to describe the disease. AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). During the initial years, therapy for AAV was limited to high dose glucocorticoids and cyclophosphamide [5,6]. Although this treatment demonstrated a high degree of clinical efficacy, pooled analysis of subsequent trial data identified significant associated risks with the majority of deaths in the first year occurring due to adverse effects of therapy [7]. Therapy of AAV has evolved over the last several decades with completion of numerous landmark clinical trials with parallel improvement in patient outcomes (Table 1). Current standard remission induction therapy for organ or life-threatening AAV centers around the use of glucocorticoids in conjunction with either cytotoxic therapy using cyclophosphamide or B-cell depleting therapy with agents such as rituximab. For less severe non-organ threatening disease a limited course of glucocorticoids alongside an anti-metabolite agent such as methotrexate or mycophenolic acid can be used [8]. In this review we aim to describe recent advancements in remission induction treatment strategies for AAV.

Glucocorticoids exert an anti-inflammatory and immunosuppressive action through regulation of gene transcription. The glucocorticoid receptor has been identified as a DNA binding protein which acts to downregulate the expression of pro-inflammatory cytokines such as IL-2, IL-6, IFN-γ and TNF-α, as well as upregulate anti-inflammatory cytokines such as IL-10 [9]. The downstream effect of this induces lymphocyte apoptosis and reduces the expression of cell adhesion molecules. This in turn reduces vasodilation and vascular permeability and T-cell migration to sites of inflammation [9]. The transrepressive effect of glucocorticoids appears to work within 18 h of administration, with sustained action up until at least 72 h [10]. Currently, glucocorticoids remain a cornerstone of AAV remission induction therapy while other induction agents take effect.

The use of glucocorticoid therapy in AAV stems from a case series of 10 patients in the late 1970s with idiopathic rapidly progressive glomerulonephritis (RPGN) [11,12]. Patients received 1 g of intravenous methylprednisolone/day for 7 days, followed by a reducing course of prednisolone starting at 80 mg/day. There was limited basis for the dosing regimen used and at the time the authors acknowledged that the side effect profile of treatment was worse than disease. Nonetheless, at a time when other therapeutic options were limited, this treatment strategy was adopted by 2 small observational studies that followed [13,14]. This formed the basis for steroid therapy in AAV and evolved to resemble the dosing protocol adopted for co-administration in subsequent trials of new induction agents and clinical practice; methylprednisolone 1 g/day for 3 consecutive days followed by 60–80 mg/day prednisolone with dose taper.

The use of steroid therapy has been associated with significant treatment-related morbidity and mortality. Data from randomized control trials (RCT) has found that the mortality rate and incident rate of serious infection is highest within the initial few months of remission induction therapy, a likely sequalae of use of high dose steroids within the first 3 months [15,16]. Follow up data from 4 landmark trials undertaken by the European Vasculitis Society (EUVAS) demonstrated treatment-related damage occurred secondary to steroids which increased over time and an association of higher levels of glucocorticoid related damage with increased duration of glucocorticoid use [17,18]. Attempts have been made to minimize steroid exposure by utilizing a combination of cyclophosphamide and rituximab with rapid dose taper of steroids to 0 within 2 weeks [19]. Initial reports found comparable outcomes to previous standard therapy, but with a reduced rate of glucocorticoid related adverse events. The efficacy of reduced dose steroids was confirmed in PEXIVAS, a large multinational landmark RCT comparing reduced dose to standard dose steroids [20]. At 3 and 6 months, the cumulative dose of oral steroids was 44% and 60% lower than standard therapy, respectively. The trial demonstrated non-inferiority of the reduced dose regime against the primary composite outcome of death from any cause or end-stage kidney disease. This was associated with a reduced rate of severe infections at year 1 (incident rate ratio 0.69, 95% CI 0.52–0.93). Most patients in the PEXIVAS trial received cyclophosphamide for induction therapy, and, consequently, concerns remained around using reduced dose regimen in rituximab induced patients. The only other trial evaluating oral glucocorticoid dosing during remission induction therapy for AAV is the LoVAS study [21,22]. This compared a reducing regimen of prednisolone starting at 1 mg/kg vs. 0.5 mg/kg alongside rituximab in a Japanese population with non-severe disease. No difference in the 6 month remission rate was identified, but a higher adverse event rate occurred in the high dose group [21]. When considering trial data from both the PEXIVAS and LoVAS, there was a marked difference in the typical cumulative dose of oral glucocorticoids, with 2240 mg and 952 mg being used, respectively. Although, it worth noting that the LoVAS study population was much smaller with only 140 patients, was representative of a specific demographic group and had a shorter follow up period than PEXIVAS. Data evaluating outcomes on the use of methylprednisolone is scarce with only 2 studies to date offering any meaningful insight on this. Both studies did not identify a salutary effect of intravenous methylprednisolone for kidney or patient survival or relapse rates but confirmed a higher rate of infection and new onset diabetes [23,24].

Summary: Reduced dose prednisone outlined by PEXIVAS has now become the standard of care while the need for and dosing of methylprednisolone warrants further study. For induction of remission in GPA, MPA and EGPA with organ/life-threatening manifestations, combination of reduced dose steroids in line with the PEXIVAS trial, alongside either cyclophosphamide or rituximab is recommended. If using rituximab in non-organ/non-life–threatening GPA/MPA a similar approach can be taken. If utilizing mycophenolate or methotrexate in such cases, high dose steroids should be used based on the available data. Although, no studies have compared glucocorticoid dosing regimens in EGPA, the PEXIVAS dosing regimens can be used for reference, bearing in mind that EGPA patients with asthma and ENT manifestations many need prolonged steroid therapy.