Background Activation of Type I interferons (IFNs) and a wide array of innate and adaptive immune mediators are hallmarks of the pathogenesis of systemic lupus erythematosus (SLE) and activation of IFN pathways correlates with disease activity.¹ In a phase 2 study of SLE patients, upadacitinib (UPA, Janus kinase inhibitor) given alone or in combination with elsubrutinib (ABBV-599, Bruton’s tyrosine kinase inhibitor) resulted in significant improvement in disease activity as measured by British Isles Lupus Assessment Group-Based Combined Lupus Assessment (BICLA) and SLE Responder Index-4 (SRI-4) at weeks 24 and 48.

Objective To evaluate the impact of UPA and ABBV599 on immunologic pathways associated with SLE pathogenesis

Methods SLE patients (n = 205) were randomized to (placebo [PBO]: n = 75; UPA 30 mg QD: n = 62; ABBV599: n = 68). At screening, patients were stratified by their SLE Disease Activity Index 2000 (SLEDAI- 2K) score, corticosteroid dose (>10-mg prednisone or not), immunosuppressant and IFN score.

Proteomic analyses were performed on the plasma samples using a commercial proximity-extension immunoassay. A repeated mixed linear model was used to compare changes in biomarkers vs PBO and Pearson’s correlation was tested to compare protein biomarkers, IFN score, and SLEDAI-2K score. All analyses were corrected for multiple testing using the Benjamini-Hochberg method. Enrichment analyses were performed to elucidate the biological pathways associated with changes in protein biomarkers.

Results As expected, elevated IFN gene expression at baseline was associated with higher SLEDAI 2K disease activity scores, increased anti-double stranded DNA titers, and lower levels of complement components. Expression of serum proteins related to the IFN pathway, such as CXCL10, sialic acid binding immunoglobulin-like lectin 1, IFN gamma, and ZBP1, positively correlated with the IFN score. Treatment with UPA monotherapy or the combination ABBV-599 significantly reduced the IFN gene scores compared with PBO at weeks 4 and 24 (P ≤ .0001). Proteomic analyses revealed 301 protein biomarkers differentially modulated at weeks 2, 12, and 24 compared with PBO, including significant downregulation of Type I IFN pathway proteins. There were additional impacts of UPA and ABBV-599 on T-cell-associated cytokines, B cells, macrophages, and innate response markers. These effects were similar with UPA and ABBV-599, suggesting that the main effect was attributable to activity of UPA.

Conclusions These results suggest that the clinical benefit demonstrated by UPA in patients with SLE includes the modulation of Type I IFN with impact on several core pathogenic pathways involved in SLE. The main biomarker effects of UPA and ABBV-599 were driven by UPA.

Reference

1. Crow MK. J Immunol. 2014;192(12):5459–68.

Conflicts of interest MCG, JF, SC, AF, TS are full-time employees of AbbVie and may hold AbbVie stock or stock options. JTM has served as a consultant and/or scientific advisor for AbbVie, Alexion, Alumis, Amgen, Astra Zeneca, Aurinia, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, GlaxoSmithKline, Lilly, Merck, Pfizer, Provention, Remegen, Sanofi, UCB, and Zenas, and has received research support from Astra Zeneca, Bristol Myers Squibb, and GlaxoSmithKline.

Acknowledgements AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approving the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship.