title: Elevated BLyS levels in patients with systemic lupus erythematosus: Associated factors and responses to belimumab.
abstract: BACKGROUND
  Patients with systemic lupus erythematosus (SLE) with B-lymphocyte stimulator (BLyS) levels ≥ 2 ng/mL are at increased risk of flare. A regression analysis was undertaken to identify routine clinical measures that correlate with BLyS ≥ 2 ng/mL. Efficacy and safety of belimumab 10 mg/kg were examined in patients with BLyS ≥ 2 ng/mL and < 2 ng/mL.
  
  
  METHODS
  Data from BLISS-52 and -76 (N = 1684) were pooled post hoc. A univariate logistic regression was employed to identify factors predictive of baseline BLyS ≥ 2 ng/mL. Factors significant at the 0.05 level then entered a stepwise logistic regression as covariates. Efficacy endpoints included SLE responder index (SRI), ≥ 4-point reduction in Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and risk of severe flare over 52 weeks. Adverse events (AEs) were analyzed for each treatment arm and BLyS subgroup.
  
  
  RESULTS
  Baseline predictors of BLyS ≥ 2 ng/mL included positive anti-Smith (≥ 15 U/mL), low complement (C) 3 (< 900 mg/L), anti-double-stranded DNA (anti-dsDNA) 80-200 and ≥ 200 IU/mL, immunosuppressant usage, proteinuria, elevated C-reactive protein (CRP), and low total lymphocyte count for all patients. Belimumab 10 mg/kg led to significantly greater SRI responses over 52 weeks versus placebo in both BLyS subgroups, though treatment differences were numerically greater at Week 52 in the BLyS ≥ 2 ng/mL group (24.1%, p < 0.0001) compared with BLyS < 2 ng/mL (8.2%, p = 0.0158). Results were similar for ≥ 4-point reduction in SELENA-SLEDAI. Risk of severe flare over 52 weeks was significantly reduced with belimumab 10 mg/kg versus placebo in the BLyS ≥ 2 ng/mL group (p = 0.0002). AEs were similar across treatment arms and BLyS subgroups.
  
  
  CONCLUSIONS
  Positive anti-Smith, low C3, anti-dsDNA ≥ 80 IU/mL, immunosuppressant usage, proteinuria, elevated CRP, and low total lymphocyte count were predictors of BLyS ≥ 2 ng/mL. Monitoring these factors could identify patients with BLyS ≥ 2 ng/mL who are at risk of flare.
authors.affiliation: Research and Development, GlaxoSmithKline, Philadelphia, PA, USA David.A.Roth@gsk.com.
authors.forename: D A
authors.initials: DA
authors.lastname: Roth
authors.affiliation: Research and Development, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Research and Development, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Research and Development, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Hammer
authors.affiliation: Research and Development, GlaxoSmithKline, Philadelphia, PA, USA.
authors.forename: C T
authors.initials: CT
authors.lastname: Molta
authors.affiliation: Research and Development, GlaxoSmithKline, Philadelphia, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gordon
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D053264:B-Cell Activating Factor / Q000097:blood* / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D016009:Chi-Square Distribution; D018450:Disease Progression; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053264:B-Cell Activating Factor; D015415:Biomarkers; D007166:Immunosuppressive Agents; C505719:TNFSF13B protein, human; C511911:belimumab
keywords: BLISS trials; BLyS; belimumab; regression analysis; systemic lupus erythematosus