ANCA-Associated Vasculitides: Future Therapeutic Strategies

Abstract

Treatment of ANCA-associated vasculitides (AAVs) has improved over the last decades. Although the agents used to treat patients contributed to that progress, it was mainly attributable to general care focusing on minimizing drug doses to prevent side effects and limit toxicities. When therapy consisted exclusively of corticosteroids (CS), 5-year survival was under 50% and the most severely ill patients died. Combining cyclophosphamide and CS represented a major therapeutic advance. Unfortunately, despite the clear remission-induction benefit obtained with immunosuppressants, their long-term side effects jeopardized outcomes, with frequently high associated morbidity and mortality. Evaluation of rituximab for remission induction demonstrated its non-inferiority vs oral cyclophosphamide. Now we must concentrate our efforts on the most severe forms of the disease, treatment of some patient subgroups, like the elderly or children, pneumo-renal syndrome, voluminous granulomatous forms, relapsing tracheal and bronchial stenoses and patients with recurrent flares despite adapted first-line treatment. In addition, eosinophilic granulomatosis with polyangiitis (EGPA), because of preexisting or simultaneous asthma and the risk of severe cardiac involvement, has specific clinical manifestations and treatment needs to be more precisely codified, perhaps adapted to pathogenetic mechanisms. Long-term treatment aims to prevent relapses, and limit sequelae and side effects. To achieve those goals, several drugs have been prescribed, mainly immunosuppressants. More recently, rituximab was shown to effectively prevent relapses and its superiority to azathioprine was proven. One major challenge in treating AAVs is to identify factors predicting relapses, which could, in the future, help choose the most appropriate drug and administration duration, thereby minimizing adverse events. Persistently unsolved questions are now more related to maintenance therapy than remission induction. The drugs available for induction - cyclophosphamide, rituximab, methotrexate - are effective but many questions remain open concerning CS management, the care of the most severe AAV forms, for instance renal insufficiency. For maintenance therapy, the major questions concern: first, the need for it, because, after rituximab-induced induction, the relapse rate is the same without maintenance or with azathioprine; second, low-dose rituximab to prevent of relapses seems of interest but long-term relapses may still occur; third, the optimal drug scheme and criteria to administer treatment or not, and at what dose. AAVs are not homogeneous diseases and treatment of granulomatosis with polyarteritis, microscopic polyangiitis and EGPA should be adapted to their individual specificities, and cannot be standardized, especially for EGPA, which has the clinical characteristics of vasculitis and asthma. Considering the overall treatment of AAVs, drivers of therapeutic choices could include, in addition to the already known items, selecting the best adapted agent(s) according to ANCA type, their presence after 12 months of follow-up, their reappearance and probably genetic markers. Indeed, we can envisage treatment tailored according to the initial ANCA subtype (anti-PR3, anti-MPO, no ANCA) and perhaps other parameters.