Systemic lupus erythematosus is a multisystem
autoimmune disease characterized by the formation of
autoantibodies that target a variety of
self antigens. B cells are fundamental to the development of these
antibodies and are a target for intervention in the disease. This review discusses four
therapies that target B cells by inducing B-cell depletion, reduction in B-cell proliferation and differentiation, or modulation of B-cell function.
Rituximab is an anti-CD20 chimeric
monoclonal antibody that depletes B cells but not plasma cells. Systematic reviews of open label studies, particularly in lupus patients refractory to conventional
therapy, have suggested that
rituximab can be an effective treatment for non-renal lupus and
lupus nephritis. However, randomized, double-blind, controlled trials comparing
rituximab with placebo in addition to standard of care
therapy for non-renal lupus and
lupus nephritis over 12 months failed to demonstrate efficacy using the planned primary endpoints, although there were some post-hoc analyses suggesting that
rituximab may have beneficial effects that would be worthy of further study as no significant toxicity has been demonstrated. Treatment with
belimumab, a humanized
monoclonal antibody targeted against
B lymphocyte stimulator (BLys), was more efficacious than placebo and had no significant increase in adverse events in two non-renal, phase III lupus trials when given in addition to standard of care
therapy for 52 weeks.
Belimumab is licensed for the management of lupus in the US and in Europe.
Atacicept is a humanized fusion
protein that binds BLys and APRIL (a proliferation-inducing
ligand) that might be more effective than
belimumab in the management of lupus. Unfortunately a phase II/III trial of
atacicept in
lupus nephritis had to be stopped due to the development of low
immunoglobulin levels and
pneumonias in some patients. However, in retrospect these complications may have been due to concomitant treatment with
mycophenolate mofetil and results of a 52-week, non-renal, phase III trial with
atacicept are awaited.
Epratuzumab is a humanized
monoclonal antibody that targets CD22 on B cells and results in modulation of B-cell function and migration, as CD22 regulates adhesion and inhibits B-cell receptor (BCR) signalling.
Epratuzumab at a cumulative dose of 2,400 mg over 4 weeks has been shown to improve lupus disease activity compared with placebo 12 weeks after initiation of
therapy in a phase II study, and a 12-month phase III study is on-going. B-cell targeted
therapies are an attractive prospect for treating lupus disease and the results of current phase III trials are eagerly awaited. Finding the most appropriate trial design to demonstrate efficacy in lupus trials has been a challenge. The SRI (SLE response index) used in the
belimumab studies and the BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment) used in the
epratuzumab studies are currently the promising trial designs for non-renal studies. For
lupus nephritis it is important that trials are of adequate duration to be able to demonstrate benefit of new
therapies over conventional
therapy.