title: The BAFFling effects of rituximab in lupus: danger ahead?
abstract: Suboptimal trial design and concurrent therapies are thought to account for the unexpected failure of two clinical trials of rituximab in patients with systemic lupus erythematosus (SLE). However, in this Opinion article we propose an alternative explanation: that rituximab can trigger a sequence of events that exacerbates disease in some patients with SLE. Post-rituximab SLE flares that are characterized by high levels of antibodies to double-stranded DNA are associated with elevated circulating BAFF (B-cell-activating factor, also known as TNF ligand superfamily member 13B or BLyS) levels, and a high proportion of plasmablasts within the B-cell pool. BAFF not only perpetuates autoreactive B cells (including plasmablasts), particularly when B-cell numbers are low, but also stimulates T follicular helper (TFH) cells. Moreover, plasmablasts and TFH cells promote each others' formation. Thus, repeated rituximab infusions can result in a feedback loop characterized by ever-rising BAFF levels, surges in autoantibody production and worsening of disease. We argue that B-cell depletion should be swiftly followed by BAFF inhibition in patients with SLE.
authors.affiliation: Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London, WC1E 6JF, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ehrenstein
authors.affiliation: Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London, WC1E 6JF, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wing
mesh_terms: D000974:Antibodies, Antinuclear / Q000276:immunology; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001323:Autoantibodies / Q000276:immunology; D053264:B-Cell Activating Factor / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D018450:Disease Progression; D005246:Feedback; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology; D000069283:Rituximab / Q000627:therapeutic use*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D017211:Treatment Failure
chemical_list: D000974:Antibodies, Antinuclear; D018501:Antirheumatic Agents; D001323:Autoantibodies; D053264:B-Cell Activating Factor; C505719:TNFSF13B protein, human; D000069283:Rituximab