Glucocorticoids (GC) remain an important therapy in remission induction and maintenance. No RCTs have been published comparing different GC dosing. In life-threatening disease or those with major organ involvement, pulsed IV methylprednisolone 0.5-1 g/day for 3 consecutive days is recommended. Most adult guidelines recommend initial GC dose of 1 mg/kg/day and tapering to a desirable level of reaching a target GC dose of 10-12.5 mg by 3-5 month. In children (<15 years old), the initial dose of oral prednisone used is 1-2 mg/kg/day with a maximum of 60 mg/day. Daily calcium (500-1000 mg) and vitamin D (1000 IU) supplementation is recommended.
Methotrexate (MTX) is recommended in combination with GC in those with limited or non-organ threatening AAV. In the NORAM trial (Non-renal Wegener's Granulomatosis Treated Alternatively with Methotrexate [MTX]), MTX was reported non-inferior to oral CYC in achieving remission induction but subsequent reports indicated less effective disease control than CYC-based induction therapy. Mycophenolate mofetil (MMF) was compared to IV CYC in non-severe GPA in MYCYC (mycophenolate mofetil versus cyclophosphamide for remission induction of ANCA-associated vasculitis) trial. MMF was noted to be non-inferior to CYC but was associated with a higher rate of relapse.
The CanVasc as well as EULAR/ERA-EDTA recommends remission maintenance treatment with a combination of low-dose glucocorticoids and either azathioprine (AZA), rituximab, methotrexate or mycophenolate mofetil. This therapy for AAV be continued for at least 24 months following induction of sustained remission.
In the Cyclophosphamide versus Azathioprine for Early Remission Phase of Vasculitis (CYCAZAREM) trial, AZA was shown to be equally efficacious as continuous CYC as maintenance treatment. This regime was also associated with fewer side-effects. MTX was shown to be well tolerated and effective in maintaining remission after induction with CYC and was proven to be of comparable efficacy to AZA. Leflunomide, though associated with increased frequency of adverse events, was found to be more effective than methotrexate in remission maintenance at a dose of 30 mg/day. Leflunomide can be used as an alternative agent in patients with intolerance to MTX and AZA. In the International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE) trial, MMF was shown to be less effective than azathioprine for maintaining disease remission.
The role of RTX in maintenance therapy has been investigated in patients with AAV after inducing remission either with CYC or RTX. It is considered a safe and effective alternative to AZA. The MAINRITSAN (Efficacy Study of Two Treatments in the Remission of Vasculitis) was the first randomized trial comparing RTX (500 mg at remission, at 2 weeks and then once every 6 months till 18 months) to daily AZA (which was tapered after 12 months). Patients receiving RTX had sustained remission compared to AZA without significant adverse events. MAINRITSAN 2 (https://clinicaltrials.gov/ct2/show/NCT01731561) explores the RTX maintenance treatment based on ANCA estimation and CD19 lymphocytes. The RITAZAREM trial is planned to evaluate two remission-maintenance strategies of repeated doses of RTX compared to daily orally administered AZA for 24 months following induction with RTX.
Both the CanVasc and EULAR/ERA-EDTA guidelines recommend switching from RTX to CYC and vice versa for relapsing AAV. In those who continue to have persistent active disease, intravenous immunoglobulin may be used as an adjunctive therapy.
The role of PLEX in AAV is not well defined. It is recommended to be used for rapidly progressive glomerulonephritis in the setting of new or relapsing disease or for the treatment of severe diffuse alveolar hemorrhage. The largest trial investigating role of PLEX, the MEPEX trial (High-Dosage Methylprednisolone or Plasma Exchange as Adjunctive Therapy for Severe Renal Vasculitis) showed an increased rate of renal recovery in AAV patients presenting with renal failure when compared with intravenous methylprednisolone. However, this trial enrolled patients who were dialysis dependent or nearing end stage renal disease and it was unable to identify role of PLEX as an adjunctive to conventional therapies. Long-term follow-up of the same cohort failed to identify sustained benefit in PLEX group. PEXIVAS is an international study which enrolled patients with AAV with severe renal vasculitis and/or diffuse alveolar hemorrhage. This study aims to determine if the adjunctive plasma exchange with two oral glucocorticoid regimens (standard- and reduced-dose GC) with standard remission induction immunosuppression is effective in reducing death and end-stage renal disease.
As mentioned above, clinical trials have not been conducted in pediatric GPA. The data from ARChiVe cohort highlights use of GC and CYC pulses most commonly used as a part of induction therapy (both for GPA and MPA) followed most frequently with methotrexate as a maintenance regime. However, most pediatric patients are now treated according to the adult recommendations. Many North American centers now prefers RTX as first-line remission induction therapy in children with severe GPA or MPA as it has low toxicity profile. PLEX should be considered in children with severe pulmonary hemorrhage or rapidly progressive renal disease responding inappropriately to GC and CYC or RTX.
The better understanding of the pathogenesis of ANCA vasculitis from in vitro and animal studies have helped us to identify the targeted therapies focusing on components of innate and adaptive immune system.
Belimumab (BEL) was investigated in a phase III, multicenter randomized double-blind trial evaluating its role the maintenance of remission in GPA and MPA in combination with AZA (BREVAS: NCT01663623). In BREVAS trial, addition of BEL to maintenance therapy with AZA did not reduce the risk of relapse. Fewer relapses of vasculitis was identified in RTX induced patients compared with placebo.
Abatacept, a fusion protein co-stimulatory T cell blocker was evaluated in an open labeled study in non-severe relapsing GPA. Almost 90% patient had disease improvement and >70% patients could discontinue prednisone. The study was limited by a small sample size, continuing background DMARDS and prednisone early during the study. Abatacept is currently being investigated in a multicenter, phase III, double-blind, placebo-controlled trial in the treatment of non-severe AAV (ABROGATE: NCT02108860).
The role of blocking complement component/receptor has been explored. Avacopan (CCX168/ selective C5a receptor inhibitor) was investigated in a phase II randomized, placebo-controlled trial (CLEAR: NCT01363388). Results from this study indicate both treatment groups receiving CCX168 were non-inferior to the standard induction and high-dose prednisone. These results highlight the importance of C5a as an important inflammatory mediator in AAV and can be used in future as an alternative to the use of oral glucocorticoids. The efficacy of Avacopan is now being evaluated in a larger phase III randomized, double-blind, active-controlled study (ADVOCATE: NCT02994927). Eculizumab is a long-acting humanized monoclonal antibody targeted against complement C5 and inhibits the deployment of the terminal complement system including the formation of membrane attack complex. It has been used successfully in a case report as an add-on treatment with an excellent clinical response with complete recovery of renal function.
Gusperimus (15-deoxyspergualin) inhibits mainly T-cell maturation and cytotoxic T-cell proliferation. It was used in a small open labeled trial with high response rates in refractory GPA. Clinical trial assessing the efficacy of gusperimus compared to conventional treatment was prematurely terminated (SPARROW: NCT NCT01446211). IL-6 is expressed and produced at sites of active vasculitis and levels are increased in patients with AAV. Case reports of successful treatment with Tocilizumab have been published in literature. Clinical trial with TCZ and AAV is currently being considered.
The mortality rates reported in pediatric series are low. The French registry reported a mortality of 10% as compared to none in a single center series reported by Noone et al. and James et al. in pediatric patients with predominant AAV associated glomerulonephritis and GPA respectively. The French vasculitis study group registry reported an increased incidence of ischemic abdominal pain and damage involving the upper respiratory tract. Childhood AAV relapse rates were also reported much higher requiring longer maintenance therapy compared to adult AAV. Important morbidity associated with AAV in pediatric patients includes nasal septal perforation with saddle nose deformity, chronic sinusitis, osteoporosis, chronic kidney disease, end stage renal disease, cystitis, infertility, and avascular necrosis.
Recently published early treatment outcome data, reported under 50% of patients achieving remission at 12 months and 61% with inactive disease at 12 months. Improvement of PVAS score of at least 50% from time of diagnosis to post-induction was seen in 92% of patients. Vasculitis associated disease damage with PVDI scores >=1 was identified in more than 60% of the patient cohort early in their disease course.