Baricitinib decreases anti-dsDNA in patients with systemic lupus erythematosus: results from a phase II double-blind, randomized, placebo-controlled trial

Thomas Dörner, Ronald F van Vollenhoven, Andrea Doria, Bochao Jia, Jorge A Ross Terres, Maria E Silk, Stephanie de Bono, Peter Fischer, Daniel J Wallace, Thomas Dörner, Ronald F van Vollenhoven, Andrea Doria, Bochao Jia, Jorge A Ross Terres, Maria E Silk, Stephanie de Bono, Peter Fischer, Daniel J Wallace

Abstract

Background: Patients with systemic lupus erythematosus (SLE) have substantial unmet medical need. Baricitinib is a Janus kinase (JAK)1 and 2 inhibitor that was shown to have therapeutic benefit in patients with SLE in a phase II clinical trial. The purpose of this study was to evaluate the median change from baseline in conventional serologic biomarkers in subgroups and the overall population of baricitinib-treated patients with SLE, and the SLE Responder Index-4 (SRI-4) response by normalization of anti-dsDNA.

Methods: Data were assessed from the phase II trial I4V-MC-JAHH (NCT02708095). The median change from baseline in anti-dsDNA, IgG, and other conventional serologic markers was evaluated over time in patients who had elevated levels of markers at baseline, and in all patients for IgG. Median change from baseline for baricitinib treatments were compared with placebo. Among patients who were anti-dsDNA positive at baseline, SRI-4 responder rate was compared for those who stayed positive or achieved normal levels by week 24.

Results: Significant decreases of anti-dsDNA antibodies were observed in response to baricitinib 2 mg and 4 mg compared to placebo beginning at weeks 2 (baricitinib 2 mg = - 14.3 IU/mL, placebo = 0.1 IU/mL) and 4 (baricitinib 4 mg = - 17.9 IU/mL, placebo = 0.02 IU/mL), respectively, continuing through week 24 (baricitinib 2 mg = - 29.6 IU/mL, baricitinib 4 mg = - 15.1 IU/mL, placebo=3.0 IU/mL). Significant reductions from baseline of IgG levels were found for baricitinib 4 mg-treated patients compared to placebo at weeks 12 (baricitinib 4 mg = - 0.65 g/L, placebo = 0.09 g/L) and 24 (baricitinib 4 mg = - 0.60 g/L, placebo = - 0.04 g/L). For patients who were anti-dsDNA positive at baseline, no relationship between achieving SRI-4 responder and normalization of anti-dsDNA was observed by week 24.

Conclusions: Baricitinib treatment resulted in a rapid and sustained significant decrease in anti-dsDNA antibodies compared to placebo among those with positive anti-dsDNA antibodies at baseline, as well as a significant decrease in IgG levels in the 4 mg group at weeks 12 and 24. These data suggest that baricitinib may influence B cell activity in SLE. Further studies are needed to evaluate if reductions in anti-dsDNA levels with baricitinib treatment reflect the impact of baricitinib on B cell activity.

Trial registration: NCT02708095 .

Keywords: Baricitinib; Cytokines; JAK inhibitor; Systemic lupus erythematosus.

Conflict of interest statement

TD has received grant support from Chugai, Janssen, Novartis, and Sanofi. He has received consultancy support from AbbVie, Celgene, Eli Lilly and Company, Janssen, Novartis, Roche, Samsung, and UCB, and speaker bureau fees from Eli Lilly and Company and Roche. RFV has received consultancy support from AbbVie, Biotest, BMS, Celgene, Crescendo, Eli Lilly and Company, GSK, Janssen, Merck, Novartis, Pfizer, Roche, UCB, and Vertex. AD has received consultancy support from GSK, Eli Lilly and Company, and Celgene and has speaker bureau fees from GSK, Pfizer, Roche, and Janssen. DJW has received consulting support from Amgen, Eli Lilly and Company, EMD Merck Serono, and Pfizer. BJ, JRT, MS, SB, and PF are employees and shareholders of Eli Lilly and Company.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Median (a) and LS mean (b) change from baseline in anti-dsDNA (IU/mL). Data were assessed for significance in patients who were anti-dsDNA positive (≥30 IU/mL) at baseline. *p ≤0.05, **p≤0.01, ***p≤0.001 for BARI vs PBO. BARI, baricitinib; LS mean, least squares mean; PBO, placebo; dsDNA, double-stranded deoxyribonucleic acid
Fig. 2
Fig. 2
Median change from baseline in IgG (a), anti-Smith (b), and anti-cardiolipin IgM (c). A Data were assessed for significance in all patients. B Data were assessed for significance in patients with anti-Smith ≥30 IU/mL. C Data were assessed for significance in patients with anti-cardiolipin IgM>12 MPL at baseline. *p ≤ 0.05, **p ≤ 0.01 for BARI vs. PBO. BARI, baricitinib; Ig, immunoglobulin; PBO, placebo; MPL, IgM phospholipid units
Fig. 3
Fig. 3
Median change from baseline in C3 (a) and C4 (b). Data were assessed for significance in patients with C3<90 mg/dL, or C4<10 mg/dL at baseline. BARI, baricitinib; C, component; PBO, placebo
Fig. 4
Fig. 4
Normalization (defined by a reduction of anti-dsDNA levels to

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