Gene Expression and Pharmacodynamic Changes in 1,760 Systemic Lupus Erythematosus Patients From Two Phase III Trials of BAFF Blockade With Tabalumab

Abstract

Objective: To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52-week, randomized, placebo-controlled, double-blind studies in which patients were treated with the BAFF-blocking IgG4 monoclonal antibody tabalumab.

Methods: Patient samples were obtained from SLE patients from the ILLUMINATE-1 and ILLUMINATE-2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0 and NanoString.

Results: At baseline, expression of the interferon (IFN) response gene was elevated in patients compared with controls, with 75% of patients being positive for this IFN response gene signature. There was, however, substantial heterogeneity of IFN response gene expression and complex relationships among gene networks. The IFN response gene signature was a predictor of time to disease flare, independent of anti-double-stranded DNA (anti-dsDNA) antibody and C3 and C4 levels, and overall disease activity. Pharmacodynamically induced changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin genes, and were consistent with other pharmacodynamic changes including anti-dsDNA antibody, C3, and immunoglobulin levels.

Conclusion: SLE patients demonstrated increased expression of an IFN response gene signature (75% of patients had an elevated IFN response gene signature) at baseline in ILLUMINATE-1 and ILLUMINATE-2. Substantial heterogeneity of gene expression was detected among individual patients and in gene networks. The IFN response gene signature was an independent risk factor for future disease flares. Pharmacodynamic changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.

Trial registration: ClinicalTrials.gov NCT01205438 NCT01196091.

© 2016, American College of Rheumatology.

Figures

Figure 1

Estimation of the interferon (IFN) response gene signature in 164 individual prespecified genes. A total of 1,760 patients (881 from ILLUMINATE‐1 and 879 from ILLUMINATE‐2) and 60 control subjects were studied. A and B, The 164 prespecified genes are represented on the x‐axes; control subjects and patients are represented on the y‐axes for ILLUMINATE‐1 (A) and ILLUMINATE‐2 (B). At least 3 broad patterns of gene expression can be visualized on both 164‐gene expression heatmaps, although when reduced to a 34‐gene signature this could be clearly discerned as high and low expression subgroups. C, Distribution of IFN response gene expression among patients and controls. Of the 1,760 patients studied, 75% had elevated expression of IFN response genes compared with healthy controls (see Patients and Methods for additional details). Data are depicted at the top as a box plot, where the box represents the 25th to 75th percentiles, the line within the box represents the median, and the lines outside the box represent the 10th and 90th percentiles. The diamond represents results from healthy controls.

Figure 2

Characterization of network connectivity between highly expressed interferon (IFN) response genes. As shown by the lines connecting individual genes, a network of highly correlated genes is expressed in the systemic lupus erythematosus (SLE) cohorts, the majority of which have been identified previously as IFN response genes. There is, however, substantially greater complexity of the IFN network than has been previously described (for additional information, see Patients and Methods, and Supplementary Material, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.39950/abstract). Briefly, the Weighted correlation network analysis module (“Yellow module”) containing this network is correlated with all 3 clinical end points: (IFN signature [ρ = 0.90, P < 2 × 10−308], Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index [ρ = 0.22, P = 5 × 10−21], anti‐DNA activity [ρ = 0.32, P = 4 × 10−43]) (see Supplementary Figure 2 and Supplementary Table 3, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.39950/abstract) and is enriched for the MetaCore‐defined SLE disease pathway (P = 1.14 × 10−32 by hypergeometric test) and the gene ontology (GO) “response to type I interferon” gene set (GO:0034340 [P = 6.60 × 10−36]) (see Supplementary Figure 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.39950/abstract).