Background/Purpose: Identification and validation of potential serologic biomarkers of clinically meaningful SLE flare are major unmet medical needs in clinical practice and trials. The purpose of this analysis was to examine biomarker predictors of SLE flares at baseline in the combined placebo groups from the phase 3 belimumab BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials.

Methods: The BLISS trials enrolled patients with active SLE (SELENA-SLEDAI ≥6) who were autoantibody positive (antinuclear antibody or anti-double-stranded DNA [anti-dsDNA]), on stable standard SLE therapy for 30 d, and without severe active lupus nephritis or CNS SLE. Patients were randomized to placebo, or belimumab 1 or 10 mg/kg, plus standard therapy. Changes in prednisone were allowed early in the trials, but had to be within 25% or 5 mg of baseline dose. Flare was defined as the development of 1 new British Isles Lupus Assessment Group (BILAG) A or 2 new B organ domain scores; any new BILAG A score; or according to the modified severe SLE Flare Index (SFI). Laboratory biomarkers evaluated included antinuclear antibody, anti-dsDNA, anti-Smith, complement (C) 3 and 4, C-reactive protein (CRP), proteinuria >0.5 g/24 h, immunoglobulin, B- and T-cell subsets, and B-lymphocyte stimulator (BLyS) quartile levels. The proportion of placebo patients with abnormal laboratory values who developed a new flare was compared with the proportion without a flare. Meaningful difference was defined as: a ≥10% absolute difference (% flare – % no flare) or nominal pvalue for pairwise comparison (likelihood ratio test); or a ≥50% increase ([% flare – % no flare]/% no flare). Study limitations: laboratory tests were defined as categorical variables (present/absent at baseline), and the time-varying nature of the characteristics over the 52 wk was not examined.

Results: By wk 52 in the placebo group (n = 562), 32% of patients (n = 180) had 1 new BILAG A or 2 new B scores; 23% (n = 130) had a BILAG A score; and 24% (n = 133) had a severe SFI flare. Predictors of wk-52 flare (% with vs without flare) are shown in the table. 

Conclusion: SLE patients on standard therapy with low C3 or C4, elevated CRP, proteinuria >0.5 g/24 h, positive anti-dsDNA, or serum BLyS ≥2 ng/mL were at increased risk for SLE flare over 52 wk. The 3 flare definitions had high concordance regarding predictors; univariate risk factors, with the exception of C3/C4, were the same for all flare definitions at 52 wk. The data suggest serologic tests predict clinically meaningful flare over 52 wk of standard SLE therapy, and may be useful in the identification of patients at greater risk for flares in clinical practice and trials.

Univariate Analysis of Predictors of 52-Wk Flare
	% 1 New BILAG A or 2 New B Scores		% Any BILAG A Score		% Severe SFI Flare
Baseline Laboratory Value	With (n = 180)	Without (n = 382)	With (n = 130)	Without (n = 432)	With  (n = 133)	Without (n = 429)
Low C3 <90mg/dL	52.8#	40.1	51.5	41.9	59.4#	39.4
Low C4 <16mg/dL	61.1+	50.5	60.8	51.9	63.2*	51.0
CRP >3mg/L	43.4+	34.9	46.0*	35.2	44.6*	35.5
Proteinuria ≥0.5g/24 h	29.5+	17.3	32.3#	17.8	32.3#	17.7
Positive anti-dsDNA (>200 IU/mL)	44.4#	28.0	46.2#	29.4	49.6#	28.2
Serum BLyS ≥2 ng/mL	35.8#	20.1	37.8#	21.3	41.7#	19.9
#p <0.001; +p <0.01; *p <0.05.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/baseline-laboratory-characteristics-from-the-combined-placebo-groups-in-the-phase-3-belimumab-trials-are-predictive-of-severe-flare-at-52-weeks/