Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus

Authors

  • William Stohl,

    Corresponding author
    1. Los Angeles County + University of Southern California Medical Center and University of Southern California Keck School of Medicine, Los Angeles
    • Division of Rheumatology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR 711, Los Angeles, CA 90033
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  • Falk Hiepe,

    1. Charité–Universitätsmedizin Berlin, Berlin, Germany
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    • Dr. Hiepe has received consulting fees from Human Genome Sciences, Inc. and GlaxoSmithKline (less than $10,000 each).

  • Kevin M. Latinis,

    1. University of Kansas Medical Center, Kansas City
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    • Dr. Latinis has received consulting fees and speaking fees from Human Genome Sciences, Inc. and GlaxoSmithKline (less than $10,000 each).

  • Mathew Thomas,

    1. Kerala Institute of Medical Sciences, Trivandrum, Kerala, India
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  • Morton A. Scheinberg,

    1. Hospital Abreu Sodré Pesquisa Clínica, São Paulo, Brazil
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  • Ann Clarke,

    1. McGill University Health Centre–Montreal General Hospital, Montreal, Quebec, Canada
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    • Dr. Clarke has received consulting fees from Human Genome Sciences, Inc. (less than $10,000) and GlaxoSmithKline (more than $10,000).

  • Cynthia Aranow,

    1. The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York
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    • Dr. Aranow has received an honorarium from Human Genome Sciences, Inc. (less than $10,000) for teaching a session at a professional meeting.

  • Frank R. Wellborne,

    1. Houston Institute for Clinical Research, Houston, Texas
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    • Dr. Wellborne has received consulting fees from Human Genome Sciences, Inc. and GlaxoSmithKline (less than $10,000 each) and research support from Human Genome Sciences.

  • Carlos Abud-Mendoza,

    1. Hospital Central Dr. Ignacio Morones Prieto, San Luis Potosi, Mexico
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  • Douglas R. Hough,

    1. Human Genome Sciences, Inc., Rockville, Maryland
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    • Drs. Hough, Pineda, Migone, Zhong, and Freimuth own stock or stock options in Human Genome Sciences, Inc.

  • Lilia Pineda,

    1. Human Genome Sciences, Inc., Rockville, Maryland
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    • Drs. Hough, Pineda, Migone, Zhong, and Freimuth own stock or stock options in Human Genome Sciences, Inc.

  • Thi-Sau Migone,

    1. Human Genome Sciences, Inc., Rockville, Maryland
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    • Drs. Hough, Pineda, Migone, Zhong, and Freimuth own stock or stock options in Human Genome Sciences, Inc.

  • Z. John Zhong,

    1. Human Genome Sciences, Inc., Rockville, Maryland
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    • Drs. Hough, Pineda, Migone, Zhong, and Freimuth own stock or stock options in Human Genome Sciences, Inc.

  • William W. Freimuth,

    1. Human Genome Sciences, Inc., Rockville, Maryland
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    • Drs. Hough, Pineda, Migone, Zhong, and Freimuth own stock or stock options in Human Genome Sciences, Inc.

  • W. Winn Chatham,

    1. University of Alabama at Birmingham
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  • on behalf of the BLISS-52 and BLISS-76 Study Groups


  • ClinicalTrials.gov identifiers: NCT00424476 and NCT00410384.

Abstract

Objective

To assess the effects of the B lymphocyte stimulator (BLyS)–specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients.

Methods

Pooled data from 2 phase III trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, comparing belimumab 1 mg/kg or 10 mg/kg versus placebo (plus standard SLE therapy for each group) were analyzed for changes in autoantibody, immunoglobulin, and complement levels. BLISS-76 patients were also analyzed for changes in B cell and T cell populations and effects on prior vaccine-induced antibody levels.

Results

Belimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies and improvement in C3/C4 levels, resulting in greater positive-to-negative conversion rates for IgG anti–double-stranded DNA (anti-dsDNA), anti-Sm, anticardiolipin, and anti–ribosomal P autoantibodies and normalization of hypergammaglobulinemia and low C3/C4 levels. Belimumab-treated patients experienced significant decreases in the numbers of naive and activated B cells, as well as plasma cells, whereas memory B cells and T cell populations did not decrease. Belimumab did not substantially affect preexisting antipneumococcal or anti–tetanus toxoid antibody levels. Post hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P ≤ 0.01) who were anti-dsDNA positive and had low C3/C4 levels at baseline. Normalization of the C3 or anti-dsDNA level by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks.

Conclusion

Belimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.

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