SP0120 Current controversies in the use of rituximab for induction and maintenance of aav disease

Rituximab has now taken one of the first places in induction remission treatment of ANCA-associated vasculitides (AAVs) and is challenging cyclophosphamide. Rituximab is an anti-CD20 IgG1 mouse–human chimeric antibody that selectively depletes mature and memory B-cells. Use of rituximab for induction In AAVs, rituximab non-inferiority to cyclophosphamide as induction agent was clearly established. In the RAVE trial, which compared oral cyclophosphamide to rituximab as induction regimen, the remission rate at 6 months was 64% in the rituximab group and 53% in the cyclophosphamide group. Consequently, rituximab has revolutionised AAVs’ standard-of-care and is now recommended as first-line therapy for many patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The RAVE trial prospectively compared two arms: induction with glucocorticoids combined with oral cyclophosphamide for 3–6 months followed by 12–15 months of azathioprine versus glucocorticoids and rituximab (375 mg/m 2 /week for 4 consecutive weeks) followed by placebo. At 12 and 18 months respectively, 48% and 39% of the rituximab–placebo recipients had sustained complete remission vs. 39% and 33% of the cyclophosphamide–azathioprine group. Those outcomes demonstrated that, after rituximab induction, azathioprine maintenance therapy is not useful. Nonetheless, both groups still had very high relapse rates, meaning that an effective maintenance regimen had not yet been found. In contrast, these findings in induction phase could not be applied to AAVs forms excluded from the RAVE study, i.e. EGPA, vasculitis associated with anti-glomerular basement membrane antibodies (Goodpasture’s syndrome), patients with alveolar haemorrhage requiring mechanical ventilation or those with rapidly progressive renal failure with creatinine exceeding 350 micromol/L. Also, studies are lacking to demonstrate that rituximab should be recommended as first-line therapy for patients who do not require cyclophosphamide for remission induction or patients with predominant granulomatous manifestations (granulomatous ear, nose and throat (ENT) lesion(s), isolated tracheal or bronchial stenosis, orbital tumour or pachymeningitis) that are life-and/or function-threatening. Use of rituximab for maintenance The idea to maintain remission with low-dose rituximab every 6 months for 18 months seemed reasonable than no intervention, as shown by MAINRITSAN trial results. In that prospective RCT, rituximab maintenance consisted of semestrial 500 mg infusions for 18 months. The first rituximab infusion was given 3–4 weeks after the end of cyclophosphamide induction therapy, followed by the second 2 weeks later and semestrial infusions thereafter. At the end of follow-up, 28 months post-randomization and 10 months after the last rituximab infusion, 5% of rituximab recipients vs. 28% of azathioprine-treated patients had relapsed. Prolonged follow-up of those patients showed that, at 60 months, although relapses had occurred in both groups, rituximab remained superior to azathioprine for sustaining remission. Although the results highlighted rituximab superiority in maintaining remission, it also became clear that relapses still occurred, frequently 18 to 24 months after the last rituximab infusion. An answer to the optimal rituximab duration will be partially obtained with the MAINRITSAN 3 trial (ongoing), which is comparing, after randomization, four additional semestrial rituximab infusions (500 mg) to placebo, after patients had previously received rituximab during 18 months. It seems reasonable that, in the future, treatment duration will be adapted to prognostic factors and predictors of relapses. Also, the impact of using higher dose of rituximab during maintenance will be addressed by the RITAZAREM trial (ongoing). This protocol evaluates rituximab infusions of 1 gram every 4 months for 20 months compared to oral azathioprine. Use of rituximab for EGPA Data on rituximab’s clinical benefits for eosinophilic granulomatosis with polyangiitis (EGPA) patients is currently restricted to low-evidence–based open-label studies and case reports. The main findings of these studies indicate a potential benefit in severe refractory/relapsing EGPA, especially in patients with positive ANCA. Two ongoing prospective studies in France are comparing rituximab to conventional immunosuppressants as induction (REOVAS trial) and maintenance phase (MAINRITSEG trial). It will help to define more precisely the indication of rituximab in EGPA patients and eventually highlight which patients would benefit from the drugs. Disclosure of Interest None declared