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. 2017 Jul 28;4(1):e000206.
doi: 10.1136/lupus-2017-000206. eCollection 2017.

Identification of biomarkers of response to abatacept in patients with SLE using deconvolution of whole blood transcriptomic data from a phase IIb clinical trial

Somnath Bandyopadhyay  1 , Sean E Connolly  2 , Omar Jabado  1 , June Ye  3 , Sheila Kelly  2 , Michael A Maldonado  4 , Rene Westhovens  5 , Peter Nash  6 , Joan T Merrill  7 , Robert M Townsend  8
Affiliations

Identification of biomarkers of response to abatacept in patients with SLE using deconvolution of whole blood transcriptomic data from a phase IIb clinical trial

Somnath Bandyopadhyay et al. Lupus Sci Med. .

Abstract

Objective: To characterise patients with active SLE based on pretreatment gene expression-defined peripheral immune cell patterns and identify clusters enriched for potential responders to abatacept treatment.

Methods: This post hoc analysis used baseline peripheral whole blood transcriptomic data from patients in a phase IIb trial of intravenous abatacept (~10 mg/kg/month). Cell-specific genes were used with a published deconvolution algorithm to identify immune cell proportions in patient samples, and unsupervised consensus clustering was generated. Efficacy data were re-analysed.

Results: Patient data (n=144: abatacept: n=98; placebo: n=46) were grouped into four main clusters (C) by predominant characteristic cells: C1-neutrophils; C2-cytotoxic T cells, B-cell receptor-ligated B cells, monocytes, IgG memory B cells, activated T helper cells; C3-plasma cells, activated dendritic cells, activated natural killer cells, neutrophils; C4-activated dendritic cells, cytotoxic T cells. C3 had the highest baseline total British Isles Lupus Assessment Group (BILAG) scores, highest antidouble-stranded DNA autoantibody levels and shortest time to flare (TTF), plus trends in favour of response to abatacept over placebo: adjusted mean difference in BILAG score over 1 year, -4.78 (95% CI -12.49 to 2.92); median TTF, 56 vs 6 days; greater normalisation of complement component 3 and 4 levels. Differential improvements with abatacept were not seen in other clusters, except for median TTF in C1 (201 vs 109 days).

Conclusions: Immune cell clustering segmented disease severity and responsiveness to abatacept. Definition of immune response cell types may inform design and interpretation of SLE trials and treatment decisions.

Trial registration number: NCT00119678; results.

Keywords: DMARDs (biologic); autoimmune diseases; systemic lupus erythematosus.

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Conflict of interest statement

Competing interests: SB, SEC, OJ, SK, MAM and RMT are employees and shareholders of Bristol-Myers Squibb. JY is an employee of Bristol-Myers Squibb. RW has received grant/research support from Roche and UCB, is a consultant for Bristol-Myers Squibb, Galapagos and Janssen, and has participated in a speakers’ bureau for Bristol-Myers Squibb. PN has no conflicts of interest. JTM has received consulting fees from Abbott, Amgen, Astellas, Bristol-Myers Squibb, Cephalon, Eisai, EMD Serono, Genentech/Roche, Human Genome Sciences/GlaxoSmithKline, Lilly, MedImmune/AstraZeneca, Ono, Pfizer, Questcor, UCB, and research grants from Genentech/Roche, Pfizer and UCB.

Figures

Figure 1
Figure 1
SLE deconvolution patient clusters and representative immune cell types (A), and distribution of patients by SLE deconvolution cluster and treatment group—all randomised and treated patients* (B, C). *Data from five randomised and treated patients excluded due to site non-compliance. Ig, immunoglobulin.
Figure 2
Figure 2
Total BILAG score (A), anti-dsDNA autoantibodies* (B), complement component 3 (C) and complement component 4 (D) at baseline. *Positive if >5.4 U/mL. Anti-dsDNA, anti-double-stranded DNA; BILAG, British Isles Lupus Assessment Group.
Figure 3
Figure 3
Mean change from baseline over time in BILAG score,* adjusted for baseline BILAG score, by SLE deconvolution cluster (LOCF analysis)—all randomised and treated patients.† *Using a numerical scoring system: A=9, B=3, C=1, D or E=0. †Data from five randomised and treated patients excluded due to site non-compliance. BILAG, British Isles Lupus Activity Group; LOCF, last observation carried forward.
Figure 4
Figure 4
Kaplan–Meier plot of time to first occurrence of new SLE flare in the double-blind period by SLE deconvolution cluster—all randomised and treated patients.* *Data from five randomised and treated patients excluded due to site non-compliance.
Figure 5
Figure 5
Median percentage change in complement components 3 and 4 over time by SLE deconvolution cluster—all randomised and treated patients.* *Data from five randomised and treated patients excluded due to site non-compliance.
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