Emerging Therapies in Antineutrophil Cytoplasm Antibody-Associated Vasculitis

Shunsuke Furuta; David Jayne


Curr Opin Rheumatol. 2014;26(1):1-6. 

In This Article

B Cell-Targeted Therapies

A rationale for B cell-targeted therapy in AAV has emerged from the presence of B cells at the sites of inflammation,[12,13] correlation of B-cell activation with disease activity in GPA,[14] the efficacy of cyclophosphamide which is a relatively B-cell-specific immunosuppressant,[15] and the contribution of autoantibodies, MPO-ANCA/proteinase 3 (PR3)-ANCA, to the pathogenesis.[16,17] CD20 is an antigen expressed on the surface of B cells, and rituximab is an anti-CD20 monoclonal antibody depleting B cells. Following several case series studies with promising results, two randomized trials evaluated rituximab for remission induction in new and relapsing patients. Both the RAVE[18] and RITUXVAS[19] trials showed similar remission rates for newly diagnosed patients between rituximab and cyclophosphamide based regimens when combined with high dose glucocorticoids. The RAVE trial also demonstrated superiority of rituximab for relapsing disease. However, no differences in safety were observed between treatment groups suggesting that high-dose glucocorticoids are currently the main modifiable contributor to adverse events in AAV.

Rituximab as remission induction therapy is indicated for relapsing AAV and newly diagnosed AAV, when cyclophosphamide avoidance is desirable. Follow-up of the RAVE trial demonstrated noninferiority of a single course of rituximab to cyclophosphamide followed by azathioprine in remission maintenance at 18 months;[20] however, relapses were frequently observed 6–12 months after a single rituximab course, specially after B cell-return.[20,21] Optimal remission maintenance therapy after rituximab-based remission induction is unclear. In the retrospective studies of relapsing AAV, repeat dosing of rituximab appears to reduce relapse risk either using time-based rituximab re-treatment[21,22] or re-treatment based on ANCA-return and B cell-return,[23] though it was also reported that a small group of patients showed persistent hypogammaglobulinemia and frequent infection after repeated rituximab infusions. The randomized trials MAINRITSAN and RITAZAREM (ClinicalTrials.gov number; NCT00748644 and NCT01697267, respectively) are evaluating efficacy and safety of repeat time-based rituximab as maintenance therapy in newly diagnosed and relapsing AAV after cyclophosphamide or rituximab-based induction, respectively.

B-cell activating factor (BAFF) is an important molecule for the survival and maturation of B cells, and serum BAFF levels are elevated in GPA patients.[14] Belimumab, an anti-BAFF monoclonal antibody, is another B cell-targeted biologic agent. The BAFF receptor is expressed in many stages of the B cell lineage including plasma cells; notably, this differs from CD20 that is not expressed by plasma cells. It is currently approved for systemic lupus erythematosus, and is in development as a relapse prevention therapy for AAV in the BREVAS trial (ClinicalTrials.gov number; NCT01663623).

CD22 is a molecule expressed on the surface of mature B cells, and acts as a negative regulator of B cell receptor signal transduction. Epratuzumab is an anti-CD22 monoclonal antibody. It acts more as an immunomodulatory agent inducing B-cell energy, not only as a cytotoxic agent with no complement-dependent cytotoxicity (CDC) and less antibody-dependent cellular cytotoxicity (ADCC), whereas rituximab acts essentially as B cells depleting agent with CDC and ADCC. Preliminary efficacy of epratuzumab for other autoimmune diseases such as lupus has been reported;[24,25] it might have potential as another B cell targeting agent in AAV.