Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Belimumab, a BLyS-Specific Inhibitor, Significantly Reduced Autoantibodies, Normalized Low Complement, and Reduced Selected B-Cell Populations in Patients with Seropositive Systemic Lupus Erythematosus (SLE): The Phase 3 BLISS Studies.

Stohl12,  W., Hiepe1,  F., Thomas8,  M., Scheinberg2,  M. A., Clarke9,  A. E., Aranow10,  C., Jimenez4,  R.

Charité Universitätsmedizin, Berlin, Germany
The Feinstein Institute for Medical Research, Manhasset, Manhasset, NY
UAB Arthritis Clinical Intervention Program, Birmingham, AL
USC Keck School of Medicine, Los Angeles, CA
Hospital Abreu Sodré Pesquisa Clínica, Sao Paulo, SP, Brazil
Hospital Central y Facultad de Medicina, San Luis Potosi, Mexico
Hospital G. Fricke, Vina del Mar, Vina del Mar, Chile
Houston Institute for Clinical Research, Houston, TX
Human Genome Sciences, Inc, Rockville, MD
Human Genome Sciences, Inc, Rockville, Rockville, MD
Kerala Institute of Medical Sciences, Trivandrum, India
McGill University Health Centre, The Montreal General Hospital, Montreal, QC, Canada

Purpose:

To assess the effects of belimumab on biomarkers, and B- and T-cell populations in patients with seropositive SLE.

Methods:

In 2 randomized, double-blind, placebo-controlled phase 3 studies (BLISS-52, NCT00424476; and BLISS-76, NCT00410384),1684 seropositive (ANA >=1:80 and/or anti-dsDNA >=30 IU/mL) SLE patients with SELENA-SLEDAI >=6 on stable standard-of-care (SOC) therapy >=30 d received belimumab 1 or 10 mg/kg, or placebo, plus SOC, on d 0, 14, and 28, then q28d for 48 wk in BLISS-52 and 72 wk in BLISS-76. Immunoglobulin (Ig), complement (C), and autoantibodies (anti-dsDNA, ANA, anti-Sm, anti-CL, anti-ribosomal P) were evaluated. In addition, B- and T-cell subsets were evaluated in BLISS-76.

Results:

Overall, belimumab treatment reduced autoimmune antibody titers and promoted conversion from antibody seropositive to seronegative status (table). More patients treated with belimumab converted from positive to negative for anti-dsDNA, anti-Sm, anti-ribosomal P, and aCL-IgG compared with placebo. Belimumab-treated patients had significantly greater increases in C3 and C4 levels with a dose response; patients receiving 10 mg/kg had significantly greater increases at every visit through wk 52 and a greater % achieved normalized levels (table). Normalization of hypergammaglobulinemia (>=16.2 g/L) occurred in significantly more patients in the 2 belimumab groups vs placebo (49.2% vs 19.7%; table). Belimumab significantly reduced various circulating B-cell subsets, but not T-cell subsets. Reductions in naïve B-cells and short-lived plasma cells (CD20-/27BRIGHT), as well as the SLE B-cell subset (CD19+/27BRIGHT/38BRIGHT), were observed as early as wk 8 with the 10-mg/kg dose. Memory B-cells increased ~100% by wk 8 and gradually decreased toward baseline levels through wk 52. A modest expansion of T-cell subsets was observed at wk 52, but this is considered to be a secondary effect of the B-cell reductions.

Conclusions:

In these phase 3 studies, belimumab treatment led to rapid, significant, and sustained reductions in autoantibodies, and normalization of C3, C4, and hypergammaglobulinemia compared with placebo. These findings, and the selective reduction of B-cell and short-lived plasma cell subsets, are all consistent with the mechanism of action of belimumab.

Table. Biomarker Data at Wk 52

 SOC + Placebo SOC + Belimumab SOC + Belimumab
 n=562n=55910 mg/kg n=563
Autoantibodies shift from positive at baseline to negative at wk 52
Anti-dsDNAa
  Positive patients, median % change-10.2-36.6*-40.8*
  Positive to negative19/280 (6.8%)47/314 (15.0%)***50/313 (16.0%)***
  Negative to positive14/143 (9.8%)9/134 (6.7%)4/134 (3.0%)*
Anti-Smb
  Positive patients, median % change-29.6-39.1**-53.6*
  Positive to negative22/120 (18.3%)32/125 (25.6%)42/131 (32.1%)*
aCL IgGc
  Positive patients, median % change-22.7-30.8*-32.1*
  Positive to negative34/85 (40.0%)63/96 (65.6%)***48/86 (55.8%)*
Anti-ribosomal Pd
  Positive patients, median % change-8.2-35.7**-54.0*
  Positive to negative16/74 (21.6%)25/69 (36.2%)31/60 (51.7%)***
Normalization of low complement at wk 52
C3en=176n=193n=202
  Median % change2.2%14.7%*17.0%*
  % normalized30/176 (17.0%)51/193 (26.4%)*77/202 (38.1%)*
C4fn=218n=246n=259
  Median % change12.9%37.5%*50.0%*
  % normalized40/218 (18.3%)86/246 (35.0%)*115/259 (44.4%)*
Ig at wk 52
  IgGn=424n=447n=448
  Median % change from baseline-2.5%-13.8%*-15.3%*
  % normalized38/193 (19.7%)91/185 (49.2%)*97/197 (49.2%)*
B-cell, median % change at wk 52n=275n=271n=273
  CD20+-9.17%-46.1%*-46.1%*
  CD20+/69+ activated-15.8%-40.5%-45.1%*
  CD20+/27+ memory0.0%50.0%*35.3%*
  CD20+/27- naïve-8.9%-66.7%*-69.6%*
  CD20-/27BRIGHT plasma-1.2%-11.3%-35.4%**
  CD20-/138+ plasma-0.3%-21.6%-34.9%**
  CD20+/138+ plasmacytoid-14.4%-50.6%***-64.4%*
  CD19+/27BRIGHT/38BRIGHT6.1%-23.7%-38.5%***
T-cell, median % change at wk 52n=275n=271n=273
  CD3+/4+-2.6%15.1%***9.5%*
  CD3+/8+-3.2%10.0%***10.8%**
  CD3+-4.2%11.8%***11.9%**
  CD4/CD8R1.9%3.9%3.7%
aAnti-dsDNA; positive (>=30 IU/mL), negative (<30 IU/mL);banti-Sm: positive (>=15 U/mL), negative (<15 U/mL);caCL IgG: positive (>=10 GPL U/mL), negative (<10 GPL U/mL);danti-ribosomal P: positive (>25 EU/mL), negative (<=25 EU/mL);eC3: normal/high (>=900 mg/L), low (<900 mg/L);fC4: normal/low (<=16 mg/dL), high (>16 mg/dL).*p < 0.05**p < 0.01***p < 0.001*p<0.0001.

To cite this abstract, please use the following information:
Stohl, W., Hiepe, F., Thomas, M., Scheinberg, M. A., Clarke, A. E., Aranow, C., et al; Belimumab, a BLyS-Specific Inhibitor, Significantly Reduced Autoantibodies, Normalized Low Complement, and Reduced Selected B-Cell Populations in Patients with Seropositive Systemic Lupus Erythematosus (SLE): The Phase 3 BLISS Studies. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1146
DOI: 10.1002/art.28912

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