RESEARCH - B-cell-targeted therapy for systemic lupus erythematosus [Rituxan (rituximab)/anti-CD20 therapy]

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Drugs. 2006;66(15):1933-48.

B-cell-targeted therapy for systemic lupus erythematosus.

University of Rochester School of Medicine, Rochester, New York, USA.

Systemic lupus erythematosus (SLE) is a complex disease characterised by

numerous autoantibodies and clinical involvement in multiple organ systems.

The immunological events triggering the onset of clinical manifestations

have not yet been fully defined, but a central role for B cells in the

pathogenesis of this disease has more recently gained prominence as a result

of research in both mice and humans. Both antibody-dependent

and -independent mechanisms of B cells are important in SLE. Autoantibodies

contribute to autoimmunity by multiple mechanisms, including immune

complex-mediated type III hypersensitivity reactions, type II

antibody-dependent cytotoxicity, and by instructing innate immune cells to

produce pathogenic cytokines such as interferon-alpha, tumour necrosis

factor and interleukin-1. Suggested autoantibody-independent B-cell

functions include antigen presentation, T-cell activation and polarisation,

and dendritic-cell modulation. Several of these functions are mediated by

the ability of B cells to produce immunoregulatory cytokines, chemokines and

lymphangiogenic growth factors, and by their critical contribution to

lymphoid tissue development and organisation, including the development of

ectopic tertiary lymphoid tissue. Given the large body of evidence

implicating abnormalities in the B-cell compartment in SLE, a recent

therapeutic focus has been to develop interventions that target the B-cell

compartment by multiple mechanisms.Rituximab, a mouse-human chimeric

monoclonal antibody against CD20 that specifically depletes B cells, has

been studied the most extensively. Although promising open-label data await

confirmation in ongoing multicentre placebo-controlled trials, a number of

preliminary conclusions can be drawn. The adequacy of peripheral B-cell

depletion depends on achieving high and sustained serum rituximab

concentrations, pharmacokinetics that can be varied with treatment dose and

factors that may affect drug clearance, such as human anti-chimeric

antibodies. In SLE patients with effective B-cell depletion, the clinical

response can be significant, with favourable responses observed in a diverse

array of disease manifestations. Moreover, rituximab appears to have the

potential to induce clinical remission in severe, refractory disease. B-cell

depletion has the potential to induce disease amelioration by inhibiting

autoantibody production and/or by interfering with other B-cell pathogenic

functions. The fact that clinical improvement correlates with B-cell

depletion and precedes by several months any decline in serum levels of

relevant autoantibodies suggests a predominant effect of

autoantibody-independent functions of B cells, although the subset of

patients with disease remission ultimately also experience autoantibody

normalisation. Significant questions remain about rituximab therapy in SLE,

including the immunological determinants of treatment response and

remission, the role of combination therapy, and the safety of repeated

courses of rituximab. In addition, the efficacy and role of other

B-cell-depleting approaches, such as humanised anti-CD20 antibodies and

anti-CD22, remain to be defined.Another B-cell-targeted therapeutic approach

is to block costimulatory interactions between T and B cells. Blockade of

the CD40-CD40 ligand pathway has met with variable clinical benefit and

unfortunate thromboembolic complications, although inhibition of the B7

pathway with cytotoxic T-lymphocyte antigen-4Ig is currently under early

investigation in SLE clinical trials. Preliminary data on the treatment of

SLE with belimumab, a fully human monoclonal antibody that specifically

binds to and neutralises the B-lymphocyte stimulator (BLyS or

B-cell-activating factor [bAFF]), are now available. In a phase II

double-blind, placebo-controlled trial of the safety and efficacy of three

different doses administered in addition to standard therapy, belimumab was

well tolerated but reportedly did not meet primary efficacy endpoints.

Blockade of BAFF is still viewed as a promising therapeutic approach and

additional agents that interfere with the BAFF pathway are under

study. Overall, therapies targeting B cells appear to be promising in the

treatment of SLE, provide additional evidence for the importance of B cells

to disease pathogenesis, and will continue to elucidate the diverse roles of

B cells in this disease.

PMID: 17100405

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus & db=pubmed & cmd=R\

etrieve & dopt=abstractplus & list_uids=17100405

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