Advances in therapeutic treatment options for ANCA-associated vasculitis

ABSTRACT

Introduction: ANCA-associated vasculitis (AAV) is a group of life-threatening autoimmune conditions that require a combination of treatments for induction and maintenance therapy. High-dose glucocorticoids and cyclophosphamide have traditionally been the mainstay of AAV treatment. During the last decade, rituximab has proven to be an effective alternative to cyclophosphamide. Currently, significant research in alternative therapeutic options for both induction and maintenance treatment is underway.

Areas covered: Guideline review of remission, induction, and maintenance therapy of AAV. Examination of current research on alternative advanced therapeutics, specifically, the evidence for rituximab, C5a inhibitors, and trimethoprim-sulfamethoxazole.

Expert opinion: Toxicities of existing therapies for AAV need to be limited, with alternative methods and agents for induction and maintenance. Importantly, the side-effects of high dose and long-term steroids have now been recognized. Newer induction agents and maintenance regimes will lead the future of AAV treatment.

KEYWORDS:

• ANCA-associated vasculitis
• drug therapy
• remission induction
• maintenance therapy

1. Introduction

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of systemic autoimmune disorders that predominately affect the small vessels. AAV are necrotizing vasculitides that are differentiated from other small vessel vasculitis by the lack of significant immune deposition in the vessel walls. AAV includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The autoantibodies that define AAV are myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA [1,2].

AAV are rare autoimmune conditions with a combined estimated prevalence of 46–184 per million [1]. However, they are associated with significant mortality. GPA mortality is reported to be greater than 90% at 2 years if left untreated [3,4]. Fortunately, the introduction of effective therapeutics has dramatically increased the 2-year survival rate to 85% [5].

The treatment of AAV comprises of remission induction followed by a maintenance phase. The treatment recommendations for induction, maintenance, or relapsing AAV vary based on the severity of the disease [3,6]. There are different definitions for determining what constitutes severe disease, but generally, any AAV that is life- or organ-threatening is considered severe [7]. Current treatments options are effective; however, they are associated with significant patient morbidity due to treatment-related adverse effects. New therapies with fewer toxic effects are needed. This article will provide a review of current treatment options and an expert opinion on the future of AAV treatment.

2. Treatment overview

2.1. Induction of remission

2.1.1. Glucocorticoids

Glucocorticoids (GC) are the mainstay of treatment for AAV despite high-dose GC being well known for their significant side-effects. Immune suppression is the most significant adverse effect, with infection being the leading cause of mortality in the first year after the diagnosis of AAV patients on GC therapy [8]. High-dose GC are also associated with adverse metabolic effects, such as weight gain and diabetes mellitus, as well as a significant increase in the risk of cardiovascular disease [9]. The high morbidity related to treatment, has guided the AAV research field. To reduce exposure to GC, steroid reducing methods are being investigated to determine the lowest dose that maintains therapeutic efficacy.

The Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody-Associated Vasculitis (PEXIVAS) trial, attempted to determine the efficacy of treatment with reduced dose GC but with a focus on severe AAV. The PEXIVAS trial compared standard GC treatment to a reduced dose GC regime. Specifically, both cohorts were tapered from a 1 mg/kg daily GC starting dose to a 5 mg daily dose over 6 months. However, the low-dose GC cohort followed a rapid de-escalation schedule with an approximate 55% reduced cumulative dose of GC than the standard controls. This is achieved through weekly rapid dose reduction early in the 6-month course. For example, at week 4 patients in the standard dose cohort received a 50 mg/day GC dose compared to similarly weighted patients in the rapid de-escalation cohort that received a 20 mg/day dose [10]. The PEXIVAS trial concluded that the reduced dose GC regime was noninferior to standard dosing when comparing the incidence of death and end-stage kidney disease. As expected, the reduce dose GC regime had a lower incidence of serious infection within the first year of treatment [11].

Similarly, the Low-dose Glucocorticoid Vasculitis Induction Study (LoVAS) is an ongoing trial which aims to determine if the use of rituximab (RTX) instead of cyclophosphamide (CYC) for remission induction allows for a reduced dose of GC with similar efficacy. The LoVAS trial is using a decreased dose of 0.5 mg/kg daily of prednisolone rather than the standard 1 mg/kg daily dose. The trial is limited to patients with mild-moderate AAV. The final results of the LoVAS trial are not yet available [12].

To induce remission in severe AAV physicians often use high dose IV methylprednisolone (MP) pulses before beginning the standard GC dosing of 1 mg/kg/day. This is reflected in the Canadian Vasculitis Research Network (CanVasc) AAV treatment guidelines which state that an IV MP pulse of 0.5–1 g/day, for up to 3 days, may precede oral GC in patients with a life-threatening disease and/or major organ involvement [7]. In clinical practice, the dosing and use of an IV MP pulse varies between clinicians [9]. The use of an IV MP pulse before oral GC results in a higher cumulative dose and thus a higher risk of treatment-related morbidity. A retrospective study conducted by Ma et al. [13] in 2017 suggested that an IV MP pulse may be associated with better renal outcomes in their patients (mainly in MPO-ANCA associated vasculitis). Conversely, a more recent retrospective study by Chanouzas et al. [8] was conducted to determine the benefit of an IV MP pulse on overall survival, renal function, and relapse rates when used as an adjuvant to standard therapy in severe disease. Based on the outcomes in their study, Chanouzas et al. [8] concluded that the use of pulse IV MP did not improve clinical outcomes and was associated with higher infection risk.

The optimal GC taper schedule that sustains remission with minimal treatment-associated morbidity is still under investigation. Currently, the CanVasc guidelines recommend maintaining high-dose GC for a maximum of 1 month before beginning a gradual taper [7]. European League Against Rheumatism (EULAR) guidelines recommend a target prednisone dose of 7.5–10 mg at 3 months [3]. Neither guideline provides a specific GC taper rate.

Rapid taper regimes are being trialed as a method of decreasing cumulative exposure to GC. A pilot trial by Miloslavsky et al. [14] studied the efficacy of RTX induction treatment with a rapid, 8-week GC taper by measuring remission rates at 24 weeks. The 8-week taper results were then used in a secondary analysis of the Rituximab versus Cyclophosphamide in AAV (RAVE) study, which had a similar RTX induction treatment but with a gradual, 5.5-month taper of GC. Miloslavsky et al. [14] concluded that in the rapid taper cohort there was a decrease in adverse events attributed to GC treatment, however there was also an increase in relapse events compared to the gradual taper used in the RAVE study. Subgroup analysis showed that the rate of increased relapse was highest in patients with severe AAV; therefore, further research is recommended on the efficacy of a rapid taper regime, perhaps with a special focus on low-risk AAV patient populations, who may derive the most benefit [14].

A recent study conducted by Pepper et al. [15] tested more extreme GC rapid taper regimes of 2- or 3-weeks duration. In this trial the GC were given in combination with RTX/CYC for remission induction in patients with severe AAV. The remission rates of the GC rapid taper cohorts were used for a post hoc comparison to the patient outcomes of EUVAS trials. The study concluded that the remission rates of the 2-week rapid taper regime were comparable to the EUVAS trial results within the 12-month follow-up period [15]. Expectedly, both Miloslavsky [14] and Pepper et al. [15] demonstrated that a rapid taper regime of GC decreased the treatment-related adverse events, specifically resulting in lower infection rates and lower incidence of new-onset diabetes. However, both trials were significantly limited due to the use of the EUVAS and RAVE trials as control groups [14,15]. Randomized control trials are needed to generate a consensus on the speed and duration of GC taper.

2.1.2. Cyclophosphamide

While GC are the backbone of treatment for AAV, it was not until CYC was introduced as a combination therapy that the mortality dramatically decreased. Combing CYC and GC therapy has increased the rate of remission to 93% [4]. However, much like GC, CYC has significant treatment-related morbidity and there has been a drive to reduce patient exposure. Some serious long-term adverse effects associated with CYC are hemorrhagic cystitis, gonadal dysfunction, bladder malignancies, leukemia, and lymphoproliferative malignancies [4].

The CYCLOPS randomized control trial determined that pulse IV CYC was as effective as an oral treatment but was associated with less treatment-related leukopenia because of a lower cumulative dose, when given as induction therapy and for 3 months after remission [16]. A long-term follow-up study of the CYCLOPS trial concluded that there was a higher rate of relapse with pulse IV CYC than an oral formulation, but this did not significantly affect mortality [17]. Therefore, the CanVasc guidelines allow physician discretion in the choice between oral or pulse IV CYC [7].

Later the CORTAGE trial assessed the efficacy of pulse IV CYC at lower, fixed doses. The experimental cohort received a 9-month GC treatment regime with six, 500 mg fixed-dose IV CYC pulses, every 2–3 weeks, then alternative maintenance therapy. The control group received a 26-month GC treatment with 500 mg/m² IV CYC pulses, every 2–3 weeks, until remission. In this study, the patient population was limited to patients older than 65 because they are at high risk of serious treatment-related adverse events. The trial results suggest that the reduced GC dosing with lower, fixed-dose IV CYC pulses had similar remission rates and a lower instance of serious treatment-related adverse events [18].

2.1.3. Rituximab

RTX is a monoclonal antibody that depletes the CD20-positive B-cells of the immune system. RTX was introduced to treatment guidelines in 2016 to reduce the adverse effects of CYC [3]. The RAVE and Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis (RITUXVAS) randomized control trials concluded that treatment of severe AAV with RTX and GC is as efficacious as standard therapy with CYC and GC but limits patient exposure to toxic side effects of CYC. However, there were similar rates of early treatment-related adverse events and mortality in both the RTX and CYC treatment regimes [19–21]. At present, the CanVasc guidelines still recommend CYC as the primary treatment of AAV due to the high cost of RTX and similar frequency of short-term treatment-related adverse events. In patients wishing to persevere fertility, however, RTX is the primary treatment [7].

Recently, post hoc analysis on the results of the RAVE and RITUXVAS studies have indicated that in specific populations RTX may be more efficacious than a CYC remission induction protocol. Specifically, ANCA autoantibodies may be an indicator for targeted therapy. Secondary analysis completed by Miloslavsky et al. [22] and Unizony et al. [23] on the results of the RAVE study concluded that PR3-ANCA patients responded more favorably to RTX induction therapy compared to CYC induction therapy. Therefore, physicians treating severe PR3-ANCA positive patients may consider the use of RTX before CYC treatment regimes.

Finally, combing RTX and CYC with standard GC induction treatment has proven to be efficacious [20,21,24–26]. The advantage of combination therapy is a decrease in cumulative cytotoxic CYC exposure and a faster GC taper regime. The CycLowVas trial found a lower rate of relapse with combination RTX and CYC treatments with lower cumulative GC exposure than the EUVAS trial results. The decreased rate of relapse may be due to a synergist effect between RTX and CYC which prolongs the length of B-cell depletion [26]. As well, Contazar et al. [24] suggested that the combination therapy had a faster rate of remission than the RAVE trial. However, the combination of CYC and RTX had an increased rate of neutropenia and subsequently more serious infections [24]. Additionally, both CYC and RTX have been shown to cause hypogammaglobulinemia which may be associated with severe infectious complications. Patients with hypogammaglobulinemia secondary to previous CYC treatment can have a further significant decline of serum immunoglobulin concentration after starting RTX treatment [27]. Therefore, the EULAR guidelines recommend patient’s immunoglobin levels should be investigated after CYC and subsequent RTX treatments [3].

2.1.4. C5a inhibitors

In 2007, Huugen et al. [28] reported that, in an animal model, inhibiting the complement system using antibodies to C5 blocked the induction of AAV. Importantly, Schreiber et al. [29] demonstrated that C5a plays an important role in the activation of neutrophils and that inhibition of C5 ameliorates outcomes in an AAV animal model [28,29]. Based on these observations, C5a inhibitors are currently being investigated as a potential treatment for AAV and as a GC sparing medication [30]. The CLEAR trial has been studying the efficacy of an oral C5a receptor antagonist, avacopan. The CLEAR trial is testing two avacopan treatment regimes in combination with either RTX or CYC induction. The first experimental group was treated with avacopan and reduced dose of prednisone. The second group was treated with avacopan without any glucocorticoids. A standard high-dose prednisone regime acted as a control group. In both experimental groups, avacopan proved to be noninferior to high-dose GC controls. At 12-weeks follow up, avacopan was found to improve albuminuria significantly more than GC treatment [31]. However, GC can increase glomerular permeability to proteins [32,33]. Therefore, this result may reflect changes in renal physiology caused by GC rather than better inhibition of renal inflammation by avacopan. Finally, avacopan was well tolerated and had less adverse treatment-related events. Specifically, avacopan had less onset of diabetes mellitus, weight gain, and psychiatric disorders than the GC control. Currently, the CLEAR study has only completed a phase 2 trial, with limited participants and a short 12-week follow-up duration. A phase 3 trial (ADVOCATE) has been performed [31]. In this trial (NCT02994927), 331 people with ANCA vasculitis were randomly assigned to either avacopan or prednisone in combination with the standard-of-care for 52 weeks [34]. Avacopan was statistically non-inferior to the current standard-of-care, with 72.3% of avacopan-treated patients and 70.1% of standard-of-care patients (control group) achieving remission at 26 weeks. Sustained remission at 52 weeks was observed in 65.7% of the avacopan-treated group versus 54.9% in the control group, which was a significant improvement. Additional benefits observed in the avacopan group patients included a reduction in glucocorticoid-related toxicity, significant improvement in kidney function in those with kidney disease, and improvements in health-related quality of life. Serious adverse events were reported in fewer patients in the avacopan group (42%) than in the standard-of-care group (45%). These initial results indicate that C5a inhibitors may be an exciting new steroid-sparing agent.

2.1.5. Mycophenolate mofetil

Mycophenolate mofetil (MMF) is an oral, lymphocyte suppressor that is generally well tolerated [35]. MMF has been recommended as an alternative to RTX in patients with mild AAV by the EULAR guidelines [3]. Following initial results that suggested MMF induced a sustained remission [36], two recent trials assessed MMF as an alternative of CYC [6,35]. The first study, by Tuin et al. [6], compared MMF and GC induction treatment to standard CYC/GC therapy, in patients with a severe relapse. It was found that MMF was not as effective as CYC in severe relapsing disease; therefore, its role was found to be limited to the treatment of selected AAV patients with non-life threatening relapses [6]. The second study, by Jones et al. [35], included 140 patients with AAV. This trial was limited to mild-moderate AAV and excluded patients with life-threatening disease or with a rapid decline in renal function. Jones et al. [35] concluded that MMF is a safe and efficacious alternative to CYC in mild-moderate AAV; however, during the MMF treatment, an increased rate of relapse was observed. These studies provide further evidence that MMF is an effective treatment alternative for CYC but should be limited to specific populations with mild-moderate disease activity and without risk factors for the frequently relapsing disease [35,37]. This conclusion is in line with the EULAR recommendations, which suggest limiting MMF use to patients with mild disease severity [3].

2.1.6. Plasma exchange

The use of plasma exchange in the treatment of AAV has become controversial recently with the landmark results of the PEXIVAS trial [11]. Earlier, in 2007, the results of the Methylprednisolone versus Plasma Exchange (MEPEX) trial concluded that plasma exchange was more effective than an IV MP pulse [38]. This resulted in EULAR adopting a recommendation for the use of plasma exchange in severe AAV and for AAV patient with alveolar hemorrhage [3]. However, the results of the PEXIVAS trial conclude that plasma exchange does not reduce the risk of end-stage renal disease or death [11]. Based on these results, the role of plasma exchange will likely be limited to AAV patients with progressive disease despite standard induction therapy or in select AAV patients who are also positive for anti-glomerular basement membrane antibodies [3,39]. Also, within the subgroup of AAV complicated by pulmonary hemorrhage there is a potential benefit from the addition of plasma exchange to standard therapy [40].

2.1.7. Intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) is being studied as a therapeutic option because of its proposed interference in ANCA binding and inhibition of ANCA-induced neutrophil activation [41]. It was first studied by Jayne et al. [41] who suggested that the use of a single course of IVIg (0.4 g/kg for 5 days) reduced disease activity in patients with refractory AAV. However, this reduction was not sustained for more than 3 months after the IVIg treatment [41]. Recently, a systematic review on the evidence for IVIg by Shimizu et al. [42] suggests that IVIg treatment was associated with improvements in disease activity and a decrease in CRP. At present, IVIg is being used when a short-term amelioration of disease activity is needed without increasing the risk of opportunistic infections.

2.1.8. Trimethoprim-sulfamethoxazole

Trimethoprim-sulfamethoxazole (TMP-SMX) is an antimicrobial agent used in AAV treatment for pneumocystis jirovecii (PCJ) prophylaxis. Moreover, a role for TMP-SMX has been suggested as an effective induction monotherapy in GPA patients with AAV confined to the upper airway (i.e., so-called loco-regional GPA). The less toxic side effect profile of TMP-SMX makes it an appealing treatment for this population [43].

2.1.9. Methotrexate

Methotrexate (MTX) has been evaluated as an induction treatment but was found to have limited efficacy. The Non-renal Wegener’s Granulomatosis Treated Alternatively with Methotrexate (NORAM) study compared MTX to a CYC control arm each combined with a standard GC induction regime. The MTX group had higher rates of relapse and MTX was less effective at remission induction in patients with the more extensive non-renal disease. Still, the NORAM trial suggested that MTX may have a role in early AAV to avoid the cytotoxic effects of CYC [44]. However, a 6-year follow-up study completed by Faurschou et al. [45] determined that the MTX cohort had higher rates of relapse, increased disease activity whereas the rate of treatment-related serious infections did not differ between the two groups. Therefore, we conclude that MTX is not an effective induction therapy, although there might be a role for the treatment of active non-severe AAV (i.e., AAV without renal and/or major organ involvement).

2.2. Maintenance therapy

2.2.1. Glucocorticoids

Several medications have proven to be effective maintenance treatment; however, very few can be used as monotherapy and most require combination with low-dose GC. Similar to GC induction therapy, the use of GCs for maintenance therapy has significant debate regarding the length and dosing of treatment post-induction. CanVasc guidelines recommend GC should be tapered to a dose of 5–10 mg/day within 3 to 6 months of achieving remission, but has no recommendation for when to discontinue GCs entirely [7]. The EULAR guidelines recommend that treatment continues for at least 24 months post-remission [3]. The Steroid Tapering in ANCA Vasculitis Evaluation Study (STAVE) has completed a meta-analysis of the length of GC maintenance treatment and rate of relapse. The study concluded that there was a significant variation of GC discontinuation time with a mean treatment length of 14.3 months and that long-term GC maintenance therapy was associated with reduced relapse rates. The STAVE trial highlights that randomized control trials are needed to determine the optimal GC maintenance duration [46].

One such randomized control trial, currently underway is The Assessment of Prednisone in Remission (TAPIR) trial. The TAPIR trial (NCT01933724) is studying GPA patients with a disease flare in the last 12 months to evaluate a maintenance prednisone dose of 5 mg/day and a prednisone taper to zero. The measured outcomes of the study will be disease relapse at 6 months follow-up. The results of the TAPIR trial are not yet available [47].

2.2.2. Azathioprine and methotrexate

Once remission has been induced, which is defined by the EULAR as the complete lack of clinical disease activity, maintenance therapy should be initiated to prevent disease relapse [3]. After induction therapy with CYC-GC, the recommendations for maintenance therapy are azathioprine (AZA) or MTX, initially combined with low-dose GC [3,7]. More recently, RTX has been proven to be effective as maintenance therapy [48]. Current guidelines for maintenance therapy are merely based on two studies, the first is the Cyclophosphamide Vs. Azathioprine for Early Remission (CYCARAZEM) study, which determined that AZA was as effective and significantly less toxic than CYC maintenance therapy [49]. The second was the Wegener’s Granulomatosis Entretien/Maintenance (WEGENT) trial, a randomized control trial that compared the effectiveness of AZA to MTX as maintenance therapy. After 12 months of treatment, AZA and MTX were determined to be equally effective [3,7,50]. A recent study published by Puéchal et al. [51], reinforced the results of the WEGENT study by following-up with the participants 10 years after their initial maintenance therapy. The survival rates between the two cohorts were comparable, which confirms that MTX and AZA are equally effective [51]. However, the use of MTX is limited because it cannot be used in patients with renal impairment [3]. If neither MTX or AZA are tolerated, MMF may be used as an alternative treatment option [7]. MMF is a less effective maintenance therapy than AZA and should only be used in patients who can not tolerate the first-line therapies [52]. The role of other agents such as LEF or cyclosporin is less clear. Small studies suggested that these agents might be effective [7,53,54].

The optimal duration of MTX or AZA maintenance therapy is controversial. CanVasc guidelines recommend a minimum of 18 months after successful remission induction [7]. However, the EULAR guidelines recommend a minimum of 24 months [3]. The length of maintenance therapy is variable due to conflicting evidence about the value of long-term maintenance therapy at reducing relapse risk. A retrospective chart review of GPA patients by Springer et al. [55] concluded that there is an inverse relationship between the length of maintenance therapy and the rate of relapse. Karras et al. [56] found similar results when conducting the REMAIN trial which compared a 24-month to a 48-month AZA and prednisolone maintenance treatment regime. Karras et al. [56] concluded that continuation of GC and AZA beyond 24 months was associated with a reduction of relapse risk (63% versus 22%, respectively).

Sanders et al. [57] compared a standard AZA maintenance treatment (1.5–2.0 mg/kg) with a taper beginning 1 year after diagnosis to an extended taper regime beginning 4 years after diagnosis. Both groups had received remission induction therapy of CYC/GC and were randomized when C-ANCA was positive at the time of stable remission. Importantly, ANCA positivity at randomization was associated with relapse risk as was previously reported by Slot et al. [58]. Sanders et al. [57] also found different relapse rates between the long and short duration of maintenance regimes, 46% versus 24%, respectively; however, the results of this study were not statistically significant [57]. Similarly, de Joode et al. [59] found no statistical significance between AZA maintenance therapy duration of greater than 18 months and reduced relapse rate (45% versus 35%) in post hoc analysis of five EUVAS trials and one French Vasculitis Study Group trial.

Therefore, the optimal length of maintenance therapy remains unclear. Whereas prolonged maintenance therapy may diminish the relapse rate it is associated with adverse effects and therefore should be restricted to patients with an increased relapse profile [37].

2.2.3. Rituximab

Despite maintenance therapy, the relapse rate with MTX or AZA remains high, with relapse occurring in 50% of patients with PR3-AAV within 5 years, thus alternative medications are still being investigated [59]. Early small studies suggested RTX was as effective as AZA for maintenance therapy prompting the start of a large randomized control trial, The Maintenance of Remission using Rituximab in Systemic ANCA-Associated Vasculitis (MAINRITSAN) [48,60–62]. The MAINRITSAN trial concluded that RTX is not only an effective alternative to AZA but proved to be superior at sustaining remission. MAINRITSAN used two cohorts, one was treated with 500 mg of RTX with subsequent dosing at 2 weeks then 6, 12, and 18 months; the other was treated daily with AZA for 22 months. The cohorts were compared based on the rate of major relapse for 28 months. Both groups had similar rates of treatment-related adverse events but there was a lower rate of relapse in the RTX cohort. The MAINRITSAN trial was predominately conducted on PR3-ANCA–positive patients, therefore further evidence is needed for other AAV populations [48]. The results of MAINRITSAN are reflected in the CanVasc guidelines, which state that RTX may be used as maintenance therapy in patients with severe AAV, especially those with PR3-ANCA positive GPA [7].

Following the MAINRISTAN trial, the optimal RTX dosing regimen is still under debate [48,60–67]. Several studies have confirmed that fixed-interval RTX dosing is effective. However, Cartin-Ceba et al. [60] demonstrated, in a small study, that preemptive re-treatment decisions can be individualized based on serial B lymphocyte and PR3-ANCA monitoring. In a RCT, this approach was addressed by comparing a fixed interval RTX dosing regimen to tailored dosing for remission maintenance. The tailored dosing regimen was based on ANCA-positivity, ANCA-titer or B-cell repopulation. The tailored regimen met the non-inferiority criteria when compared to the fixed-interval dosing regimen, whereas this patient cohort received a lower number of RTX infusions [68].

After discontinuing RTX maintenance therapy there appears to be a sustained reduced rate of relapse in many AAV patients [61,64,66]. Alberici et al. [66] suggested after 2 years of fixed-dose RTX maintenance therapy, 50% of AAV patients sustain remission for more than 24 months after stopping RTX infusions. The benefit of long-term RTX maintenance treatments is therefore controversial and will be studied further in the MAINRITSAN3 (NCT02433522) which will compare whether RTX infusions should be given for maintenance treatment at 18 months or 46 months [69].

A recent randomized control trial, Rituximab versus Azathioprine After Induction of Remission with Rituximab (RITAZAREM) compared RTX to AZA maintenance therapy after RTX induction treatment for a disease relapse. As also observed in the MAINRITSAN trial, results indicate RTX had a lower relapse rate at 20 months of maintenance treatment, 13% for RTX maintenance therapy versus 38% for AZA maintenance therapy, respectively. Importantly, RTX had a lower rate of severe adverse events: 22% of patients in the RTX cohort and 36% in the AZA cohort experienced at least one severe adverse event. The RTX cohort did, however, have a higher rate of hypogammaglobulinemia than AZA (29% and 25%, respectively) but this corresponded to a minimal increase in non-severe infections in the RTX cohort compared to the AZA (49% and 48%, respectively) [70]. These results indicate that RTX is superior to AZA for maintenance therapy of AAV patients with a history of disease relapse.

2.2.4. Trimethoprim-sulfamethoxazole

Similar to its role in induction therapy, TMP-SMX has evidence for use in maintenance therapy at higher doses than for PCJ prophylaxis [43]. Stegeman et al. [71] compared TMP-SMX as an adjuvant maintenance therapy to a placebo in patients with GPA in remission. The cohort receiving TMP-SMX had a significantly lower rate of relapse. At 24 months 82% of the TMP-SMX cohort were in remission compared to 60% of the placebo group. As well, the rate of infections, both respiratory and nonrespiratory was significantly lower in the TMP-SMX cohort [71].

2.2.5. Adjuvant therapy

The upper respiratory symptoms of AAV, such as chronic nasal obstruction, epistaxis, severe nasal crusting, stuffiness, nasolacrimal duct obstruction, recurrent otitis, and recurrent sinusitis, can be difficult to treat with systemic therapy [72]. Therefore, clinicians may require adjuvant treatment options to address nasal disease symptoms. As per the EULAR guidelines, patients with GPA that are colonized with Staphylococcal aureus should receive nasal antibiotics to reduce their rate of relapse [3]. Conversely, the CanVasc guidelines suggest there is limited evidence for the use of topical antibiotics for Staphylococcus aureus infections in preventing relapse. However, they do recommend nasal and sinus rinses with saline [7]. In addition, TMP-SMX may be used [43]. Finally, budesonide respules (nebulizer suspension) may be used in selected cases [73].

3. Monitoring ANCA for relapse prevention

Monitoring ANCA levels is an attractive option for guiding therapeutics to prevent patient relapse while reducing exposure to immunosuppressive agents. First, the value of measuring ANCA for predicting relapse must be considered. Recent literature has suggested that the accuracy of ANCA in predicting a relapse is variable based on the presence or absence of renal involvement [74]. In patients without renal involvement, ANCA was not an accurate predictor of disease relapse [74]. Results from the RAVE trial also indicate that an ANCA rise is significantly associated with relapse in patients with renal involvement and/or alveolar hemorrhage [75]. Kemna et al. [37] suggested the predictive value of ANCA was associated with vasculitic disease but not with the granulomatous disease, a distinction that is difficult to apply clinically due to the limitations of obtaining a histological diagnosis. The application of monitoring ANCA rise to guide therapeutics has been investigated in several studies. Osman et al. [76] systematically reviewed these studies and concluded that future proof-of-principle trials should be performed before a treatment based on ANCA levels can be recommended. In the future, other tests that are highly correlated with relapse activity will be combined with the measurement of ANCA for therapeutic guidance [68,77–79].

4. EGPA specific therapies

The prevalence of EGPA is significantly lower than that of MPA or GPA [3]. EGPA is often excluded from many of the large randomized control trials for the treatment of AAV. Notably, the RAVE and RITUXVAS trials excluded EGPA [19,20]. This has led to a lack of strong evidence on the most efficacious therapy and currently, GC is still the mainstay of treatment [80]. If life or organ-threatening manifestations are present, immunosuppression such as CYC should be added, whereas maintenance therapy with AZA or MTX is used after induction of remission [80]. RTX has been found to be an effective remission induction agent in EGPA; however, this evidence is solely based on retrospective studies [81].

Recently, interleukin-5 (IL-5) antagonists are being investigated as an EGPA specific therapy. IL-5 stimulates eosinophilic activity and has an important role in the pathogenesis of EGPA [82,83]. Mepolizumab is a humanized monoclonal anti-IL-5 antibody that has been used in two studies as a treatment for EGPA vasculitis. Mepolizumab maintenance treatments had a higher remission induction rate, longer remission duration, and lower GC dosing requirements than the placebo group which received only prednisone. However, the positive results of mepolizumab may be inflated by the control of the asthma and sinonasal symptoms rather than vasculitic symptoms [84].

A therapeutic antibody to the IL-5 receptor benralizumab is also the subject of a current clinical trial in EGPA [85]. Alternatively, omalizumab, an IgE targeting biologic, may be used as a steroid-sparing agent. Specifically, omalizumab can reduce asthma symptoms and exacerbations in patients with EGPA [86]. Further, randomized control trials are needed to determine the role of these steroid-sparing agents in EGPA treatment.

5. Conclusion

The fundamental treatment for remission induction of AAV remains high-dose CG and CYC. Low-dose GC induction treatment is being tested by the LoVAS trial and was evaluated by the PEXIVAS trial. Alternatively, avacopam, a C5a inhibitor, is a promising new therapy that may replace high-dose CG. The landmark results of the RAVE and RITUXVAS trials concluded that RTX is an effective alternative to CYC which has led to the inclusion of RTX in AAV treatment guidelines.

For maintenance therapy, current recommendations are AZA or MTX, but RTX has also been proven to have a role as an alternative maintenance treatment. As an add-on, TMP-SMX at high doses, is an option for the frequently relapsing patient. The optimal length of maintenance treatment is still controversial, with conflicting studies being recently released.

6. Expert opinion

Both early diagnosis and better therapeutic management of patients with AAV have improved patient and renal survival over the last three decades [5]. Despite being more than 35 years since the discovery of ANCA, a major challenge in many countries is still to test for ANCA in patients that have symptoms and signs suggestive of AAV. Therefore, the education of medical students and residents is pivotal in recognizing early forms of AAV. If a diagnosis can be made at an early phase of the disease (i.e., before renal failure is present) the prognosis is excellent.

The well-documented toxicities of AAV treatment have already led to GC and CYC sparing therapies. Unfortunately, the complete replacement of high-dose GC is still not possible. However, updated AAV treatment guidelines are on the horizon. Specifically, guidelines may reflect a shift to the use of lower dose GC induction therapy. Similarly, rapid tapering of GC induction treatment will likely be incorporated into treatment recommendations. However, high-dose GCs have been fundamental to improved mortality outcomes and physicians will require strong evidence that a rapid, 8-week taper does not significantly negatively affect renal function and/or other organ damage prior to considering adopting such a recommendation. Finally, the initial research on C5a inhibitors is promising and may be an exciting solution to replace the need for high-dose GC as induction treatment.

In the future, we would anticipate protocolized steroid dosing for induction, maintenance, and flare. However, due to the challenges of studying patients with vasculitis, large trials may take years to complete.

As a result of new developments, morbidity of the disease and toxicity of treatment have gained more attention. However, patient-reported outcomes have only recently been developed and are now becoming a focus of treatment. As reported by most patients, fatigue is their most important complaint. At present, a major challenge is unraveling the pathophysiology of the fatigue that affects more than 70% of AAV patients [87].

The introduction of RTX has been an important advancement in treatment options for AAV. RTX has proven to be a strong alternative to CYC; however, the cost of RTX remains a barrier to its worldwide use. Currently, the strongest benefit to RTX is the preservation of fertility and the use of RTX in relapsing patients who received prior CYC induction therapy. RTX and CYC may be used as dual adjuvant therapy to increase the length of remission and to reduce the cumulative cytotoxic exposure. In the future, the role of RTX in maintenance therapy may expand as more studies are conducted on relapse rates and dosing regiments. The ideal length of maintenance therapy will continue to evolve as new treatment regimes are investigated and will require significant time to acquire strong evidence. Alternatively, as new less toxic maintenance treatments are introduced the optimal length of maintenance therapy may no longer be as important because cumulative exposure to maintenance treatment may result in less adverse effects.

The move to precision medicine will likely become an integral part of the treatment of AAV. The validation of MMF for select patient populations (i.e., patients with nonlife-threatening relapses) should be further validated with future randomized control trials. Also, adjuvant treatment of the upper respiratory symptoms of AAV is becoming more important since the morbidity of the ENT symptoms cannot be neglected in patients with GPA. Whereas we recommend nasal and sinus rinses with saline in all patients with GPA, local application of nasal antibiotics may be used to reduce the rate of recurrence of rhino-sinusitis. In addition, in GPA patients that have proven to have frequent relapses, TMP-SMX (2 x 960 mg dosing) may be used to prevent infections and relapses of the disease. Finally, budesonide respules may be used in selected cases. Nasal corticosteroid sprays, however, should be avoided since they increase the risk of nasal bleeds and hence of Staphylococcus aureus colonization.

ANCA remains the most important biomarker in disease classification and predicting relapses in patients with more severe vasculitic manifestations such as alveolar hemorrhage and renal vasculitis. When combined with post-translational modifications and possibly genetic backgrounds in a personalized medicine approach, ANCA titers may be more informative in predicting relapses. Future proof-of-principle studies incorporating these components may provide more insight into the role of this combined strategy in patient care and follow-up, which can then be validated in large clinical trials.

Breaking up AAV based on the ANCA serotype, into PR3-AAV and MPO-AAV, is currently mainly important for the therapy of the initial (non-renal) phases of the disease and for prevention of relapses. The discrimination between PR3-AAV and MPO-AAV might prove to be of greater significance in the scope of future clinical trials. As a consequence, we expect that new developments in laboratory medicine will be useful for treating patients based on a ‘personalized medicine’ approach in the coming years.

Article Highlights

• Review of treatment for AAV induction and remission

• Steroid use has a significant risk for adverse events

• Future for AAV treatments includes reducing steroid dose

• Novel therapies are being studied and may provide alternative treatment options

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.