Work

Effect of upadacitinib and ABBV-599 on biomarkers in SLE: results from the phase 2 SLEek study

Year: 2026

Type: article

Abstract: Objective Dual targeting of type I interferon and B-cell pathways could be a promising strategy for SLE. We examined biomarker and gene expression changes over 24 weeks in patients treated with upadacitinib, a Janus kinase (JAK) inhibitor that modulates interferon signalling, alone or in combination with elsubrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor that targets B-cell pathways.Methods SLEek ( NCT03978520), a phase 2, randomised, double-blind, placebo-controlled study, enrolled adults with moderately to severely active SLE. This analysis includes patients who received upadacitinib 30 mg (n=62), ABBV-599 (upadacitinib 30 mg plus elsubrutinib 60 mg; n=68) or placebo (n=75). Whole blood was collected at baseline (week 0) and various time points over 24 weeks to analyse serum immunoglobulins, immune cell counts and proteomic profiles. Weighted gene coexpression network analyses evaluated differentially expressed genes.Results Both upadacitinib and ABBV-599 significantly reduced and sustained lower anti-double-stranded DNA autoantibody levels compared with baseline through week 24, whereas upadacitinib monotherapy alone reduced plasma cell percentages. Proteomic analysis found modulation of 301 proteins, including reductions in interferon-related and B-cell-associated proteins. RNA sequencing revealed significant changes in interferon, plasma cells and cell cycle gene modules correlating with clinical biomarkers.Conclusions Upadacitinib was associated with a reduction in both autoantibody and B-cell activation and with key gene expression changes in SLE pathogenic pathways. Dual JAK/BTK inhibition did not provide additional impact on most immunological parameters. These findings support JAK inhibition as a targeted monotherapy for SLE.Trial registration number NCT03978520.

Source: Lupus Science & Medicine

DOI: 10.1136/lupus-2026-002162