Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) comprise granulomatosis with polyangiitis (GPA; previously referred to as Wegener’s granulomatosis), microscopic polyangiitis (MPA), eosinophilic granulomatous polyangiitis (EGPA; previously referred to as Churg-Strauss syndrome), and the so-called renal-limited vasculitis [
13]. From a clinical perspective it may be useful to think of GPA as having two forms: a predominantly granulomatous form with mainly localised disease with chronic course; and a florid, acute small vessel vasculitic form characterised by severe pulmonary haemorrhage and/or rapidly progressive vasculitis, or other severe vasculitic manifestation [
13]. These two broad presentations may co-exist or present sequentially in individual paediatric and adult patients [
13].
Therapeutic advances
Renal morbidity and mortality is a major concern in the AAV, hence therapy aimed at preservation of renal function is a recurring theme for the treatment of AAV in both adults and children [
18]. Treatment for paediatric AAV is broadly similar to the approach in adults based on evidence derived from a number of clinical trials conducted by the European Vasculitis Study group (EUVAS) [
19]. The EUVAS group was developed to conduct interventional clinical trials aimed at optimizing treatments and outcomes for vasculitis patients [
19]. A total of 12 clinical trials involving over 1300 patients have been conducted that have defined the standard of care and permitted consensus treatment recommendations [
19]. Particular areas of focus were: the reduction in cyclophosphamide exposure; efficacy of plasma exchange in reducing renal morbidity; remission maintenance strategies; and establishing the efficacy of newer therapies [
19]. Notably, two of the clinical trials have involved children with AAV. These clinical trials, and how they have informed current practice for both adults and children with AAV are summarised below.
The CYCAZAREM trial (CYClophosphamide or AZAthioprine for REMission) recruited 144 new adult patients with AAV and compared a 3–6-month cyclophosphamide course, stopping when remission was achieved, to a standard 12-month course of cyclophosphamide. Both groups were then switched to azathioprine as maintenance therapy [
20]. No differences in remission or relapse rates were observed [
20]. The validation of sequential cyclophosphamide induction followed by azathioprine maintenance has subsequently served as the basis for later trials [
20]. Pulsed IV cyclophosphamide (CYCLOPS, CYCLophosphamide Oral versus PulSed) was then shown to be as effective as daily oral cyclophosphamide, with a 50 % reduction in cumulative cyclophosphamide dose, and fewer adverse events [
21]. Based on these studies, current induction of remission therapy in adults and children with AAV includes corticosteroids and cyclophosphamide (usually 6–10 intravenous doses at 500–1000 mg/m2 [maximum 1.2 g] per dose, given every 3–4 weeks) [
13,
19]. Intravenous pulsed cyclophosphamide is increasingly favoured over oral continuous cyclophosphamide in adults and children, because the reduced cumulative dose, and less neutropenic sepsis in adult patients, albeit without good prospective paediatric evidence [
13,
19].
In addition, B-cell depletion with rituximab has been explored as an alternative to cyclophosphamide for remission induction for AAV [
22,
23]. Efficacy of this treatment approach for severe renal disease in combination with two IV cyclophosphamide doses was evaluated in the RITUXVAS trial [
23]. This regimen had no benefit over a standard IV cyclophosphamide regimen in terms of efficacy or adverse event rate; but demonstrated that rituximab could provide clinically important cyclophosphamide sparing [
23]. Another US multicentre, randomized trial compared rituximab with cyclophosphamide for remission induction, and showed that rituximab was not inferior to daily oral cyclophosphamide for induction of remission in severe ANCA-associated vasculitis; and rituximab may be superior in patients with relapsing disease [
22]. These studies led to licensing of rituximab for remission induction of AAV in adults in the USA and Europe. Whether low-dose cyclophosphamide still has a role in induction therapies alongside rituximab remains uncertain. Notably, an ongoing international multicentre study is exploring the efficacy and safety of Rituximab in children with new onset, or relapsing AAV (the PEPRS study; NCT01750697). Whilst we are encouraged that industry are supporting and undertaking paediatric studies of new therapeutic agents in rare diseases such as AAV, we appreciate that studies of “older” drugs, or studies of combination drug therapy in the paediatric population may not be feasible (due to lack of industry support), even if desirable for some diseases.
Two further EUVAS trials evaluated whether cyclophosphamide could be replaced as an induction agent, either with methotrexate or MMF. The NORAM trial (Non-Renal Alternative treatment with Methotrexate) demonstrated that remission rates for non-severe GPA/MPA were similar at 6 months between an oral methotrexate and an oral cyclophosphamide regimen; but that late relapse was more common after methotrexate [
24]. MMF also proved not inferior to an IV cyclophosphamide regimen at 6 months in the MYCophenolate mofetil versus CYClophosphamide; MYCYC), trial but with a higher relapse rate in the MMF group. The higher relapse rate was confined to the PR3-ANCA-positive subgroup, and no differences in remission or relapse rates were seen in the MPO-ANCA patient subgroup [
25]. Importantly, for the first time, children were included in the MYCYC trial [
25]. Many differences exist in physiology, pathology, pharmacokinetics, and pharmacodynamics between children and adults. Inclusion of paediatric patients in large adult RCTs, therefore, by no means eliminates the need for separate paediatric studies, but this approach at least allows us to obtain some robust paediatric data rather than just directly extrapolating from purely adult studies.
Regarding maintenance regimens, the EUVAS group found MMF not to be superior to azathioprine for relapse prevention of AAV after cyclophosphamide induction in the IMPROVE trial [
26]. MMF is therefore not recommended as a routine remission maintenance agent, but can be used when azathioprine or methotrexate have failed to maintain remission in adults and children with AAV.
Rituximab was also considered to have role in relapse prevention, and repeat-dose rituximab was shown to be associated with fewer relapses than azathioprine, following cyclophosphamide induction in the French MAINRITSAN trial [
27]. An ongoing study led by both EUVAS and the Vasculitis Clinical Research Consortium (VCRC) is exploring the role of rituximab in treatment of relapsing disease in the RITAZAREM trial (NCT01697267).
Other biologic agents that have been considered in AAV therapy are anti-tumour necrosis alpha agents, but these were largely abandoned after a negative result in relapse prevention in an etanercept study [
28]. The T-cell co-stimulation inhibitor CTLA4-Ig (abatacept) is currently being studied in a randomized trial for treatment of non-severe, relapsing GPA (ABROGATE; NCT02108860). The ALEVIATE trial (NCT01405807), a small dose-finding trial of compassionate use of alemtuzumab (a monoclonal antibody against CD-52, found on mature lymphocytes), is ongoing. For EGPA, a single-centre, phase 2, uncontrolled study demonstrated that mepolizumab (a monoclonal antibody against IL-5) allowed glucocorticoid sparing over the course of the disease in most patients, with no relapses during the active 9-month treatment phase [
29].
Lastly, the PEXIVAS trial is comparing four different therapeutic combinations in a factorial design examining a reduced oral glucocorticoid regimen with a standard-dose regimen; with or without plasma exchange for adults with AAV and renal involvement (NCT00987389). Small case series have also indicated that plasma exchange reduces renal morbidity in children with AAV [
30]; but there are no ongoing or planned trials of therapeutic plasma exchange in children with AAV.