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Novel treatments for systemic lupus erythematosus.

ABSTRACT: There are many new therapeutic directions for the disease systemic lupus erythematosus (SLE). Despite this, the US Food and Drug Administration (FDA) has approved only one biological agent and it involves B cells, now thought to play a significant role in the pathogenesis of SLE. The name of the drug is belimumab, which is an agent that removes the B-cell cytokine called B lymphocyte stimulation factor (BLyS). Rituximab did not achieve its primary endpoints, even though the consensus is that it may be effective in some forms of SLE including renal disease. The anticytokine therapies against interleukin (IL)-6, IL-10, IL-17 and tumor necrosis factor (TNF) are effective in their own ways and phase II and III trials are in progress. Of particular interest to immunologists are the anti-interferon alpha and gamma drugs, which show promise in the animal models. Modulation of costimulatory molecules; specifically, the anti CD40, CTLA-***Ig and ICOS/B7RP blockade agents offer possibilities for the future using new pathways heretofore limited to rheumatoid arthritis. Finally, the use of tyrosine kinase inhibitors is another direction that has been successful in the inhibition of SLE in the murine model; early trials in human SLE have begun.

SUBMITTER: Xiong W

PROVIDER: S-EPMC3383530 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Novel treatments for systemic lupus erythematosus.

Xiong Wen W Lahita Robert G RG

Therapeutic advances in musculoskeletal disease 20111001 5

There are many new therapeutic directions for the disease systemic lupus erythematosus (SLE). Despite this, the US Food and Drug Administration (FDA) has approved only one biological agent and it involves B cells, now thought to play a significant role in the pathogenesis of SLE. The name of the drug is belimumab, which is an agent that removes the B-cell cytokine called B lymphocyte stimulation factor (BLyS). Rituximab did not achieve its primary endpoints, even though the consensus is that it ...[more]

PMID: 22870484

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Project description:Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell transcription factors, cytokines and B cell-T cell interaction can result in aberrant B cell maturation and autoantibody production. These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients. Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications. While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells. Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation. Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell-T cell interaction. These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients. Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire. Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN. Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients.

Dataset Information

Novel treatments for systemic lupus erythematosus.

Publications

Novel treatments for systemic lupus erythematosus.

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