B cell depletion as a novel treatment for systemic lupus erythematosus: A phase I/II dose‐escalation trial of rituximab

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Safer and more effective therapies are needed for the treatment of systemic lupus erythematosus (SLE). B lymphocytes have been shown to play fundamental pathogenic roles in SLE, and therefore, elimination of B cells with the use of rituximab may represent a new therapy for SLE.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A phase I/II dose‐escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of 100 mg/m<jats:sup>2</jats:sup> (low dose), a single infusion of 375 mg/m<jats:sup>2</jats:sup> (intermediate dose), or as 4 infusions (1 week apart) of 375 mg/m<jats:sup>2</jats:sup> (high dose). CD19+ lymphocytes were measured to determine the effectiveness of B cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Rituximab was well tolerated in this patient population, with most experiencing no significant adverse effects. Only 3 serious adverse events, which were thought to be unrelated to rituximab administration, were noted. A majority of patients (11 of 17) had profound B cell depletion (to <5 CD19+ B cells/μl). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (<jats:italic>P</jats:italic> = 0.0016 and <jats:italic>P</jats:italic> = 0.0022, respectively, by paired <jats:italic>t</jats:italic>‐test). This improvement persisted for 12 months, despite the absence of a significant change in anti–double‐stranded DNA antibody and complement levels. Six patients developed human antichimeric antibodies (HACAs) at a level ≥100 ng/ml. These HACA titers were associated with African American ancestry, higher baseline SLAM scores, reduced B cell depletion, and lower levels of rituximab at 2 months after initial infusion.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Rituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B cell depletion. Based on these results, controlled trials of rituximab appear to be warranted.</jats:p></jats:sec>