Background/Purpose: Elevated Type-I interferon (IFN) signature characterizes at least 50% of adults with SLE and has been associated with autoantibodies and more severe disease in single-center studies, but association with disease severity in clinical trials of diverse populations has been controversial (Kennedy Lupus Sci Med. 2015 28;2). Therefore, we examined gene expression profiles of 1,760 randomly selected SLE patients from two worldwide Phase III trials of the anti-BAFF, IgG4 monoclonal antibody, tabalumab in SLE.

Methods: Total RNA was extracted from whole blood, collected at baseline in Tempus tubes, using the PerfectPure RNA Blood Kit. RNA quality was assessed using Ribogreen and a Bioanalyzer RNA chip. The Affymetrix WT Plus Kit was utilized for cDNA prep and labeling, and labelled cDNA was hybridized to the GeneChip Human Transcriptome Array 2. The Affymetrix HTA2.0 array has 70,753 transcript clusters. Annotation data were retrieved from Affymetrix’s na34 build (www.Affymetrix.com). Only transcript clusters that represented a single protein coding gene were considered in this analysis (n=19,818). A literature review yielded 163 reported interferon responsive genes and a subset of 34 was selected to form a pre-specified signature for analysis. Kaplan-Meier time to event analysis and Cox proportional hazards regression with backward elimination (p-leave=0.05) were conducted using baseline covariates: Type-I IFN signature, SELENA-SLEDAI, low C3, elevated anti-dsDNA antibody, race and geographic region.

Results: Using the pre-specified Type-I IFN gene signature, 75% of SLE patients in the tabalumab trials had an elevated Type-I IFN response gene signature at baseline. Type-II IFN-associated genes were also upregulated in SLE vs controls to a much lesser extent. As expected, the baseline Type-I IFN signature was associated with anti-dsDNA antibodies, low C3, low C4 and SELENA-SLEDAI score.  Severe flare, as measured by the SELENA-SLEDAI Flare Index, was observed in 16.3% and 15.8% of patients in Trial-1 and Trial-2, respectively. The Type-I IFN signature at baseline was associated with risk of developing a severe SELENA-SLEDAI flare over the ensuing 52W and time to flare was highly significant in Trial-1 (p<0.0001) and Trial-2 (p<0.001). Baseline Type-I or Type-II IFN signature was not associated with SRI-5 response to either standard of care or standard of care + tabalumab. Using Cox proportional hazard analysis, the time to SELENA-SLEDAI flare predicted by the Type-I IFN signature was found to be an independent risk factor from baseline anti-dsDNA antibodies, low C3, low C4 or baseline SELENA-SLEDAI score in both Trial-1 (p=0.0015) and Trial-2 (p=0.0002).

Conclusion: 75% of SLE patients in the tabalumab trials had elevated Type-I IFN signature at baseline, associated with anti-dsDNA antibodies, low C3, low C4, SELENA-SLEDAI score and time to SELENA-SLEDAI severe flare. Time to SELENA-SLEDAI severe flare predicted by the Type-I IFN signature was found to be an independent risk factor using a Cox proportional hazard model. SRI-5 response to tabalumab could not be predicted by the IFN signature status at baseline.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/baseline-gene-expression-profiles-in-1760-patients-from-two-phase-iii-trials-of-baffblys-blockade-in-sle/