Hallmark trials in ANCA-associated vasculitis (AAV) for the pediatric rheumatologist

Systemic vasculitis is a challenging and complex multi-organ disease that results in primary inflammation of the blood vessel wall. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of systemic vasculitides that is characterized by small-to-medium sized blood vessel inflammation with the presence of autoantibodies known as ANCA. AAV diseases include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), and Microscopic Polyangiitis (MPA). AAVs are one of the more common types of systemic vasculitis encountered by pediatric rheumatologists. Proper treatment of this condition is critical as the mortality of untreated AAV can be up to 80% [1, 2]. Given the paucity of clinical trials in pediatric AAV, pediatric rheumatologists have relied on adult AAV evidence for management. In this review, we highlight key findings of critical landmark trials in AAV for the pediatric rheumatologist.

Standardized tools are important in measuring disease activity and damage; they also help guide treatment decisions in rheumatic diseases. Numerous instruments have been developed to measure disease activity in AAV [3‐5]. These measurements are often used to define primary or secondary outcomes in AAV trials. Thus, it is important for pediatric rheumatologists to familiarize themselves with these tools.

Measurement of damage is an essential component in the follow-up assessments of chronic disease. The Vasculitis Damage Index (VDI) [11] is an unweighted scoring system comprising 64 items grouped under 11 organ-based systems. Damage is defined as an irreversible change lasting for more than 3 months. The VDI is a cumulative index and can only remain static or increase over time. The damage recorded needs to occur after the vasculitis diagnosis, but do not need to be attributable to the diagnosis (e.g. might be related to treatment).

There is no validated tool to assess disease damage in children with vasculitis. However, the Pediatric Rheumatology European Society (PRES) Vasculitis Working Group and Childhood Arthritis & Rheumatology Research Alliance (CARRA) are working toward validating a formal pediatric modification of the VDI [10] – PVDI, which has been piloted in some studies.

Treatment of AAV is generally categorized into two phases: induction and maintenance. Induction therapy refers to the therapies required to achieve disease remission. After achieving remission, maintenance therapy is initiated to prevent relapses. This review discusses induction therapy for severe and limited AAV separately, followed by maintenance therapy trials.

The European League Against Rheumatism (EULAR) has previously described more specific disease severity definitions by expert consensus in order to conduct trials with more homogeneous AAV patient populations, and to make trials comparable (Table 1) [12]. For clinically relevant purposes, severe (also described as generalized) AAV is defined as presence of life- or major organ-threatening manifestations. The Canadian Vasculitis Research Network (Canvasc) recommendations on AAV management provides clinical examples describing major organ-threatening manifestations, which may include severe and progressive kidney involvement, alveolar haemorrhage resulting in severe hemoptysis, severe gastrointestinal (e.g. intestinal bleeding), cardiac (e.g. heart failure due to pericarditis or myocarditis), central nervous system (e.g. rapidly progressive neuropathy), or ocular involvement (e.g. orbital pseudotumor) [13]. Limited AAV is often defined as localized involvement without organ-threatening manifestations. Patients with constitutional symptoms are generally included. Patients with renal or pulmonary manifestations may be included with the caveat that the organ manifestations do not result in threatened organ function (e.g. pulmonary infiltrates without severe hemoptysis or mildly reduced kidney function with a Cr < 120 without evidence of casts or significant proteinuria).

Given the concerns of utilizing CYC long-term, such as increased risk of malignancy and infertility, investigators have evaluated the use of less toxic immunosuppressants as alternatives (Table 3). In the CYCAZAREM (CYC versus AZA for Early REMission phase of vasculitis) trial, patients with a newly diagnosed severe AAV and a serum creatinine of < 500 μmol/L in whom remission had been achieved within 3–6 months, were randomly assigned to continue poCYC or switch to azathioprine (AZA) for 12 months. All subjects were then switched to a lower dose of AZA, which continued to the end of the study (18 months). Both groups continued a tapering course of corticosteroids. The primary outcome was major and minor relapse rate at 18 months. Relapse rates were not significantly different between groups [25]. There was no difference in severe AEs, although the study was not powered to detect differences in AE rates. Long-term follow-up (median 8.5 years) revealed a trend for worse outcomes in the AZA group in terms of relapses and development of ESRD but these were not statistically significant [26].

While the CYCAZAREM study validated AZA as a suitable alternative to poCYC for maintenance, the optimal duration of AZA treatment was not examined. The REMAIN (prolonged REmission-MAINtenance therapy in systemic vasculitis) trial concluded that prolonged maintenance therapy with AZA and low dose corticosteroids to 48 months from diagnosis resulted in a 3-fold reduction in the frequency of relapses compared with withdrawal of AZA and corticosteroids by 24 months [27]. Moreover, the continuation group had improved renal survival with reduced incidence of ESRD. In a RCT (AZA-ANCA trial) comparing standard and extended AZA maintenance therapy in patients with PR3-AAV, patients treated with longer treatment duration (4 years after diagnosis and tapered thereafter) had a lower relapse rate, albeit not significant, compared with those treated with standard treatment (1 year after diagnosis and tapered thereafter) [28]. However, this trial was terminated prematurely given slow patient recruitment and did not achieve an adequate sample size. Therefore, although not definitively proven, a longer duration of maintenance therapy may lead to better outcomes.

The use of MTX as an alternative maintenance agent with possibly less toxicity and equal or perhaps greater efficacy than AZA was examined in the WEGENT trial. In the WEGENT trial, AAV patients in remission were randomized to either AZA or MTX and a tapering oral steroid course [29]. The rate of AEs causing death or study withdrawal was the same between the two groups, indicating MTX was similar in toxicity with AZA. Relapse rates were also similar confirming MTX as a viable alternative to AZA. In the follow-up study, 10-year overall survival rates, total number of relapses, relapse rates and AEs did not differ significantly [30].

Other immunosuppressive agents, including MMF and leflunomide, have also been studied. The IMPROVE (International MMF Protocol to Reduce Outbreaks of Vasculitides) trial compared the efficacy of MMF versus AZA for maintenance of remission in AAV patients in whom remission had been induced with corticosteroids and CYC, with or without methylprednisolone pulses and PLEX. MMF was significantly less effective at preventing relapses when compared to AZA after a median follow-up of 39 months [31]. In a RCT comparing leflunomide and MTX, leflunomide was found to be more effective than MTX in preventing major relapses but was associated with more AEs [32].

The MAINRITSAN (Maintenance of Remission using Rituximab in Systemic ANCA-Associated Vasculitis) trial is the first RCT to evaluate RTX for maintenance therapy. After achieving remission, patients were randomly assigned to receive either RTX at 0 and 2 weeks following randomization then every 6 months until 18 months or AZA until 22 months. Both groups were treated with corticosteroids for at least 18 months. There were significantly fewer major relapses at 28 months in the RTX group compared with the AZA group (5% versus 29%) [33]. In the long-term study, RTX remained superior to AZA up to 60 months, with greater rates of relapse-free and overall survival [34]. The MAINRITSAN2 compared an individually tailored RTX regimen with fixed-schedule regimen [35]. Patients in the tailored-infusion arm received RTX at randomization and received repeat infusions based on lymphocyte counts and ANCA titers until 18 months. The fix-scheduled arm received the same regimen from the original MAINRITSAN trial. There was no significant difference between the number of relapses but the tailored-infusion arm received fewer number of infusions overall.

The BREVAS (Belimumab in Remission of Vasculitis) is a recent RCT that evaluated the efficacy of belimumab, a monoclonal antibody against B lymphocyte stimulator, as an adjunctive therapy to a regimen of AZA with low-dose corticosteroids [36]. Overall, the addition of belimumab did not reduce relapses.

Few studies have evaluated the outcomes of pediatric AAV (pAAV) or compared these with adult-onset AAV (aAAV). While some conflicting results exist, it appears that disease severity in pAAV is similar or slightly higher than in aAAV. Rottem et al. prospectively compared 23 pediatric GPA patients with 135 adult-onset patients and found that remission rates, relapse rates, and serious AE rates were similar [48]. Sacri et al. found that renal impairment occurred in 90% of pAAV at disease onset, which is more common than reports in aAAV which range from 10 to 20% at diagnosis to 60–80% during the disease course [49]. Iudici et al. compared 35 pAAV patients with 151 aAAV patients in a matched case-control study [50]. Both groups received similar induction therapy, most commonly corticosteroids and IV CYC. The authors report that by 5 years, pAAV patients had higher relapse rates, accumulated more damage, and were more likely to remain on corticosteroids and immunosuppressive agents than their adult counterparts. Eleven percent of pAAV and 9% of aAAV patients died.

To date, there have been no RCTs evaluating treatment regimens in pAAV. The four largest cohort studies assessing contemporary outcomes in pAAV found that the majority of patients received corticosteroids and CYC for remission induction, followed by AZA or MTX for remission maintenance (Table 5). The definitions and rates of remission and relapse varied between studies. Sacri et al. reported disease remission in 92% of pAAV patients, and a relapse rate of 41% [51]. In a single-centre study from Toronto [52], all 20 pAAV followed for a minimum of 6 months achieved remission; the relapse rate was 75% at a median follow-up of 10 months. Iudici et al. reported inactive disease in all pediatric EGPA and MPA patients and 68% of GPA patients at the last follow-up visit (median 96 months), however many of these patients continued to be on therapy, including many on corticosteroids [51].

The largest pAAV cohort to date, the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort [10], evaluated the outcomes of 105 pAAV patients and found that 42% achieved remission by 12 months (remission defined as PVAS of 0 on < 0.2 mg/kg/day corticosteroids or equivalent), and 61% had inactive disease on higher doses of corticosteroids. All but 3 patients in remission were on maintenance therapy at 12 months, and 48% had discontinued corticosteroids. Rates of remission were similar for those treated aggressively (CYC and/or RTX, 43%) versus moderately (MTX, AZA or MMF, 30%); those treated aggressively had higher baseline PVAS scores. Twenty-four percent of patients experienced minor relapses after achieving inactive disease. The remission rate of 42% in this study is lower than that reported in the adult studies, which ranges from 53 to 93% [14, 17, 22] but direct comparison is complicated by differences in study design, remission definitions, and corticosteroid regimens. Sixty-three percent of the ARChiVe cohort had evidence of damage by 12 months, compared to 87% reported in grouped adult data [52]. Given that we have speculated greater organ reserve in children compared to adults, this high rate of damage in children only 12 months after diagnosis is concerning and further suggests that children with AAV may have a more severe disease course than their adult counterparts.

The Single Hub and Access point for Pediatric Rheumatology in Europe (SHARE) initiative recently developed consensus-based guidelines for the management of rare pediatric vasculitides. These included recommendations for pAAV (including EGPA) along with Polyarteritis Nodosa and Takayasu Arteritis [53]. Given the paucity of pediatric-specific evidence and highly variable clinical practice amongst various centers, the aims of the recommendations were to define the minimum standard of care for these patients. A large portion of the guidelines is directed at establishing the diagnosis of systemic vasculitis in a pediatric patient.

Adult-derived literature was primarily used to address pAAV treatment recommendations, as the quality of pediatric evidence was poor and largely based on descriptive studies. Induction recommendations for severe disease largely remain similar to adult guidelines, which included corticosteroids and ivCYC as primary agents. The guidelines stress the importance of IV over PO CYC use given the lower cumulative toxicity but similar efficacy. Interestingly, PLEX was defined as a “typical” initial induction agent in severe AAV patients, while adult guidelines generally describe it as an adjunctive agent with insufficient evidence to support its use as a first-line therapy. Furthermore, while adult guidelines strongly support the use of RTX as a first-line remission induction therapy, the same recommendation was not made in the SHARE guidelines, and was considered a second or third line induction agent. Unfortunately, the guidelines do not distinguish severe from limited AAV, and do not provide any specific treatment recommendations for pediatric patients with limited disease, which could potentially lead to confusion or possible over-treatment of a unique subgroup of pAAV patients. Similar agents have been recommended for maintenance therapies.

There are questions that remain unanswered in AAV management. In the realm of induction management, LoVAS (Low-dose Glucocorticoids Plus Rituximab Versus High-dose Glucocorticoids Plus Rituximab for Remission Induction in ANCA-associated Vasculitis) is a trial currently underway to evaluate whether corticosteroid regimens can be used in lower doses when RTX is used as the induction agent [54]. The PEXIVAS study provides some preliminary suggestion that regimens utilizing lower doses of corticosteroids do not impact rates of severe outcomes (such as death or ESRD), but final results are pending [21]. The CLEAR study was a recent trial that demonstrated that Avacopan, a C5 receptor inhibitor, could potentially replace or reduce corticosteroid doses, bringing forward unique therapies with a possible steroid-sparing role [55].

With regards to maintenance, the MAINRITSAN3 is a RCT comparing RTX for 46 months compared to 18 months. The RITAZAREM trial is an ongoing study using higher dose RTX in patients with relapsing disease [56]. TAPIR (The Assessment of Prednisone In Remission Trial) is a trial comparing continuation of low-dose corticosteroid versus stopping corticosteroid entirely in GPA patients during maintenance.

Given that EGPA remains understudied in comparison to the other AAVs, further research is needed to determine the efficacy of conventional immunosuppressants and RTX in EGPA, and the optimal patient candidates and dosing regimen for mepolizumab. ANCA-negative patients, excluded by most trials to date, also remain understudied, constituting another future research priority.

Evidence-based guidelines for pAAV management remain sparse. The EULAR/EUVAS guidelines do not comment on the pediatric population. The CanVasc recommendations make 4 pediatric-specific statements, primarily suggesting that pediatric patients should be treated according to adult guidelines [35]. As previously mentioned, the SHARE guidelines for the management of pAAV have been developed in order to set the minimum standard of care when it comes to systemic vasculitis treatment [53]. The majority of treatment recommendations however, were based on low-quality pediatric evidence, expert opinion, or extrapolated from adult studies. While these recent guidelines address the pediatric rheumatology community’s desire and need for more pediatric specific recommendations [57], evaluating its uptake and usefulness is warranted. Additional multi-center studies in pAAV are required to address questions around efficacy and toxicity of existing therapies in the pediatric setting, so that pediatric guidelines may incorporate higher quality evidence.

Significant progress has been made in our understanding of the management and outcomes of AAV over the last two decades. Future studies should be directed towards addressing the remaining unanswered questions, which include determining the optimal duration and regimen of AAV induction and maintenance therapy, improving our understanding of EGPA management, and developing evidence for pAAV to better inform pediatric-specific treatment guidelines.