Ehrenstein, M

Embleton-Thirsk, A

Gordon, C

Isenberg, D

Nguyen, D

Parvaz, M

Ribeiro, L Santos

Shipa, M

English

UCL Discovery

 1 Title:  Distinct immune networks stratify organ involvement and response to B cell targeted therapies in systemic lupus erythematosus  Authors Muhammad Shipa1, Liliana Ribeiro Santos1, Dao X Nguyen1, Andrew Embleton-Thirsk2, Mariea Parvaz1, David A Isenberg1, Caroline Gordon3, and Michael R Ehrenstein1*.   1 Department of Rheumatology, University College London, London, UK 2 Comprehensive Clinical Trials Unit, University College London, London, UK  3 Rheumatology Research Group – Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham, UK  Character count (including title and figure legend and references but not including spaces): (3600 allowed)  main text 3163 reference 56 Title 109 Legend 166 Total 3494  Background We have recently completed the BEAT-lupus trial comparing belimumab vs placebo, both after rituximab, in systemic lupus erythematosus (SLE) (1).  There is a clear unmet need for biomarkers that could guide precision targeting of advanced therapies for this heterogenous disease.   Objectives  To identify biomarkers of clinical response to belimumab after rituximab in the BEAT-lupus trial.  Methods  2 We constructed a model utilising a range of clinical, coupled with routine and exploratory laboratory data, from the BEAT-lupus trial to identify variables at baseline (screening) that could predict a major clinical response (MCR, defined as reduction to BILAG C in all domains, steroid dose of ≤7.5mg/day & SLEDAI≤2, without anti-dsDNA antibody component) at 52 weeks. Relevant serum autoantibodies and cytokines were assayed by ELISA/Simoa, and interferon signatures and BAFF expression measured by RT-PCR. A linear mixed model was applied to longitudinal data collected during the trial stratified by treatment and clinical response.   Results A major clinical response (MCR) was achieved in 48% (10 responders, 11 non-responders) of patients who received belimumab after rituximab compared to 35% (8 responders, 15 non-responders) in the placebo group (i.e. rituximab alone), added to tapered standard of care, at 52 weeks. Baseline serum IgA2 anti-dsDNA antibody levels emerged as the only positive predictor of attaining MCR in belimumab treated patients (AUROC 0.8, 95% confidence interval [CI] 0.7-1.0), but negatively predicted MCR in the placebo arm (AUROC 0.2, CI 0.1-0.4). At baseline 77% and 85% of patients were positive for serum IgA2 anti-dsDNA antibodies in belimumab and placebo arms respectively, which reduced to 30% at 52 weeks in the belimumab group but remained unchanged with placebo (Fisher exact test, p=0.007). In striking contrast, the percentage of patients who remained IgG anti-dsDNA antibody positive from baseline to 52 weeks were similar between the belimumab and placebo group, despite the serum levels significantly falling in the belimumab group (1). A significant reduction in serum IgA2 anti-dsDNA antibody levels at 24 and 52 weeks from baseline was only observed in belimumab responders (Figure 1).    The number of circulating IgA2-secreting (but not total) plasmablasts (p=0.032) and T follicular helper cells (p=0.031) were significantly reduced at 52 weeks in the belimumab treated arm compared to placebo. Elevated serum IgA2 anti-dsDNA antibody levels were also associated with active renal disease (odds ratio, OR 3.2, CI 1.7-5.8, p<0.001). In contrast, serum IgA1 anti-dsDNA antibody (OR 1.3, CI 1.0-1.7, p=0.042) and interferon-alpha levels (OR 1.4, CI 1.0-2.0, p=0.041), and interferon transcriptional signature (OR 1.1, CI 1.0-1.3, p=0.027), were significantly associated with mucocutaneous disease activity but did not predict response to B cell targeted  3 therapy. Patients with a high baseline serum IL-6 were less likely to achieve an MCR irrespective of therapy (OR 0.4, CI 0.2-0.9, p=0.033). Serum IgA2 (p=0.001) and IgA1 (p=0.038) anti-dsDNA antibody levels were significantly higher in active renal and mucocutaneous disease respectively in an independent cross-sectional lupus cohort.   Conclusions IgA2 anti-DNA autoantibodies are biomarkers of renal involvement and response to belimumab after rituximab in systemic lupus erythematosus. Our study reveals distinct molecular networks associated with renal and mucocutaneous involvement, and response to B cell targeted therapies, which could guide precision targeting of current therapies for this heterogenous disease.  References: 1. Shipa M, et al. Annals of Internal Medicine. 2021;174:1647-57.  Not part of character count Funding This research was supported by Versus Arthritis (grant number 20873) and the UCLH Biomedical Research Centre (BRC). GSK provided belimumab free of charge, as well as additional funding. GSK had no role in this research and did not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Versus Arthritis and the UCLH BRC reviewed the relevant grant proposals and monitor progress of relevant aspects of the study but did not play any role in the analyses, interpretation of data, or decision to submit results.  Conflict of interest statement  MRE has received grant/research support from GSK. MRE and CG have been members of the speakers’ bureau for GSK and have received consultancy fees for attending GSK advisory boards. CG also reports personal fees for honoraria from consultancy work from the Center for Disease Control and Prevention, AbbVie, Amgen, Astra-Zeneca, EMD Serono, MGP, Sanofi and UCB, personal fees for speakers bureau from UCB and an educational grant from UCB to Sandwell and West Birmingham Hospitals NHS Trust that supported her research work.     4 DAI has received consultancy fees from Astra Zeneca, Eli Lilly, Merck Serono, Servier and UCB.     Figure 1. Percentage change in serum IgA2 anti-dsDNA antibody levels through to 52 weeks stratified by clinical response to belimumab (after rituximab) and placebo (after rituximab) at 52 weeks.   5  

DISTINCT IMMUNE NETWORKS STRATIFY ORGAN INVOLVEMENT AND RESPONSE TO B CELL TARGETED THERAPIES IN SYSTEMIC LUPUS ERYTHEMATOSUS

https://discovery.ucl.ac.uk/10159919/1/Isenberg_BEAT-LUPUS%20EULAR%20mechanism%20abstract%20FINAL.pdf

DISTINCT IMMUNE NETWORKS STRATIFY ORGAN INVOLVEMENT AND RESPONSE TO B CELL TARGETED THERAPIES IN SYSTEMIC LUPUS ERYTHEMATOSUS

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