Baseline Predictors of Systemic
Lupus Erythematosus (SLE) Flares!
Michelle A. Petri, Ronald F. van Vollenhoven, Jill Buyon, Roger
A. Levy, Sandra V. Navarra, Ricard Cervera, Z. John Zhong, and
William W. Freimuth,
Arthritis and Rheumatism August 2013
Context
! 
Flare (mild, moderate, or severe) occurring in 65–70% of
patients with SLE within 1 year
! 
Trying to identify predictors of SLE flare with inconsistent
results :
! 
! 
Absence of an accepted definition of any SLE flare
! 
However agreement on what constitutes severe flare
Studies that examined whether medications
(hydroxychloroquine / prednisone) affect SLE flare risk
produced mixed results
Objectives
! 
To identify predictors of moderate-to severe
systemic lupus erythematosus (SLE) flare in 562
patients treated with standard therapy alone in
phase III belimumab trials
! 
And to evaluate the impact of standard therapies
on preventing flares
Methods (1)
! 
Post hoc analysis :
! 
BLISS-52 and BLISS-76 patients randomized to receive standard
therapy alone
! 
BLISS-52 (n = 865) and BLISS-76 (n = 819) were multicenter,
multinational, placebo-controlled trials in which patients with
active SLE (SELENA–SLEDAI score ≥ 6 at screening) were
randomized to standard therapy plus either placebo or belimumab
! 
Inclusion criteria : autoantibody positivity (ANA titer 1:80 or anti-dsDNA level 30 IU/ml), stable
standard SLE therapy for 30 days, no severe active lupus nephritis or severe active central
nervous system lupus, no intravenous cyclophosphamide within 6 months of enrollment, and
no intravenous immunoglobulin or prednisone (100 mg/day) within 3 months
! 
Change in standard therapy were restricted after 16 weeks of treatment and prednisone dose
had to be within 25% or 5 mg of the baseline dose in the first 24 weeks
Methods (2)
! 
Baseline demographics, disease activity, and biomarkers in patients
with and those without flare at treatment weeks 24 and 52 ! 
Severe flare was defined by : ! 
! 
Modified SLE Flare Index (SFI) ! 
Development of any new BILAG A domain score
Severe and moderate flare was defined by : ! 
! 
Development of 1 new BILAG A domain score or 2 new BILAG B
domain scores
Baseline characteristics associated with a >10% absolute difference
or a >50% increase in flare rates were considered predictive
Results (1)
! 
n = 287 + 275 = 562
! 
Frequencies of flares over 52 weeks ! 
SFI (severe flare) : 23.7%
! 
Any new BILAG A domain score : 23.1%
! 
1 new BILAG A domain score or 2 new BILAG B
domain scores : 32.0%
Baseline characteristics of the patients treated with standard SLE
therapy alone in the BLISS trials
Results (2)
! 
! 
Flare predictors by univariate analysis on all 3 indices at weeks 24 and 52 were :
! 
Score >12 on SELENA–SLEDAI
! 
BILAG renal, vasculitic, and hematologic scores
! 
Anti–double-stranded DNA (antidsDNA) positivity
! 
Proteinuria (>0.5 gm/24 hours);
! 
Elevated C-reactive protein levels
! 
B lymphocyte stimulator (BLyS) levels >2 ng/ml
None of the baseline medications evaluated, including corticosteroids,
immunosuppressives, antimalarials, and other concomitant medications, predicted
flare on any index at either week 24 or week 52, with the exception of any steroid
on the SFI at week 24
Baseline disease activity in patients with and patients without flare as defined by the modified SLE Flare
Index at week 52 (A) and week 24 (B), by 1 BILAG A domain score or 2 new BILAG B domain scores at
week 52 (C), and by any new BILAG A domain score at week 52 (D)
Baseline laboratory values in patients with and patients without flare as defined by the modified SLE Flare Index
(SFI) at week 52 (A) and week 24 (B), by 1 new BILAG A domain score or 2 new BILAG B domain scores at week
52 (C), and by any new BILAG A domain score atweek 52 (D)
Baseline disease activity and biomarkers in the 562 patients with flare
by treatment week 52
Baseline SLE medication use in patients with and patients without flare as defined by the modified SLE
Flare Index at week 52 (A) and week 24 (B), by 1 new BILAG A domain score or 2 new BILAG B domain
scores at week 52 (C), and by any new BILAG A domain score at week 52 (D)
Results (3)
! 
! 
Independent predictors by multivariate analysis at week 52 : ! 
SELENA–SLEDAI and/or BILAG renal involvement and
antidsDNA>200 IU/ml (on all 3 indices)
! 
SELENA–SLEDAI and/or BILAG neurologic and vasculitic involvement
(on 2 indices: any new BILAG A domain score and 1 new BILAG A
domain score or 2 new BILAG B domain scores)
! 
BLyS levels >2 ng/ml (on 2 indices: the SFI and 1 new BILAG A
domain score or 2 new BILAG B domain scores)
! 
Low C3 level (on the SFI).
Baseline medications did not significantly decrease or increase
moderate-to-severe SLE flare risk
Predictors of flare over 52 weeks by multivariate analysis
Discussion (1)
! 
! 
Strengths :
! 
Inclusion of data from a large number of patients
! 
Use of 3 SLE flare indices (and concordance) ! 
Application of multivariate analysis
Weakness :
! 
Retrospective post hoc analysis ! 
Biomarkers validation
! 
Difference in rates of flares across the flare indices
! 
Comparaison with other study is complicatedby the differing definitions of SLE flare
! 
No any significant demographic predictor of flare (proportions of patients of African
descent ?)
Discussion (2)
! 
Previous studies :
! 
Anti-dsDNA positivity as predicting flare over the course of 1 year
! 
Increased anti-dsDNA levels preceded flare by 8–10 weeks
! 
Anti-dsDNA levels 5 times the upper limit of normal were associated with a shorter time to
first flare in patients with serologically active but clinically quiescent disease
! 
No consistent association between antidsDNA positivity or low complement levels and risk
of flare
! 
Modest predictors of SLE flare : adjusted mean SLEDAI score over 2–3 years ≥ 4 and
steroid use in the first year
! 
Maintaining hydroxychloroquine therapy was associated with reduced risk of flare short
term and long term (due to seronegatives patients ? 10-fold fewer patients ? effect of
withdrawing a maintenance treatment ? multiple treatments ?) ! 
initiating prednisone therapy based on serologic disease activity markers in clinically stable
patients reduced severe flare risk
Conclusion
! 
! 
Patients who were receiving standard SLE therapy
increased risk of clinically meaningful flare over 1 year
if they had :
! 
renal, neurologic, or vasculitic involvement
! 
elevated anti-dsDNA or BLyS levels
! 
or low C3 Hydroxychloroquine (corticosteroids,
immunosupresives) use was not predictive...