Mechanism of action of baricitinib and identification of biomarkers and key immune pathways in patients with active systemic lupus erythematosus

Abstract

Objectives: To elucidate the mechanism of action of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, and describe immunological pathways related to disease activity in adults with systemic lupus erythematosus (SLE) receiving standard background therapy in a phase II trial.

Methods: Patients with SLE were treated with baricitinib 2 mg or 4 mg in a phase II randomised, placebo-controlled study. Sera from 239 patients (baricitinib 2 mg: n=88; baricitinib 4 mg: n=82; placebo: n=69) and 49 healthy controls (HCs) were collected at baseline and week 12 and analysed using a proximity extension assay (Target 96 Inflammation Panel (Olink)). Interferon (IFN) scores were determined using an mRNA panel. Analytes were compared in patients with SLE versus HCs and in changes from baseline at week 12 between baricitinib 2 mg, 4 mg and placebo groups using a restricted maximum likelihood-based mixed models for repeated measures. Spearman correlations were computed for analytes and clinical measurements.

Results: At baseline, SLE sera had strong cytokine dysregulation relative to HC sera. C-C motif chemokine ligand (CCL) 19, C-X-C motif chemokine ligand (CXCL) 10, tumour necrosis factor alpha (TNF-α), TNF receptor superfamily member (TNFRSF)9/CD137, PD-L1, IL-6 and IL-12β were significantly reduced in patients treated with baricitinib 4 mg versus placebo at week 12. Inflammatory biomarkers indicated correlations/associations with type I IFN (CCL19, CXCL10, TNF-α and PD-L1), anti-double stranded DNA (dsDNA) (TNF-α, CXCL10) and Systemic Lupus Erythematosus Disease Activity Index-2000, tender and swollen joint count and worst joint pain (CCL19, IL-6 and TNFRSF9/CD137).

Conclusion: These results suggest that baricitinib 4 mg downregulated key cytokines that are upregulated in patients with SLE and may play a role in a multitargeted mechanism beyond the IFN signature although clinical relevance remains to be further delineated.

Trial registration number: NCT02708095.

Keywords: cytokines; inflammation; systemic lupus erythematosus.

Conflict of interest statement

Competing interests: TD has received grant support from Chugai, Janssen, Novartis and Sanofi, 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. YT has received speaking fees and/or honoraria from Gilead, AbbVie, Behringer-Ingelheim, Eli Lilly and Company, Mitsubishi-Tanabe, Chugai, Amgen, YL Biologics, Eisai, Astellas, Bristol-Myers, Astra-Zeneca, received research grants from Asahi-Kasei, AbbVie, Chugai, Mitsubishi-Tanabe, Eisai, Takeda, Corrona, Daiichi-Sankyo, Kowa, Behringer-Ingelheim, and consultant fees from Eli Lilly and Company, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GSK, AbbVie. MP has received grants and consulting fees from Eli Lilly and Company. ERD, AEK, MES, JART, JTS, ZS, and IDLT are employees and shareholders of Eli Lilly and Company.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Correlation between key analytes and the IFN signature. Line of regression and confidence intervals are shown for CCL19 (A), CXCL10 (B), TNF-α (C), and PD-L1 (D) and the IFN signature. CCL19, C-C motif chemokine ligand 19; CXCL10, C-X-C motif chemokine ligand 10; IFN, interferon; PD-L1, PDCD1 ligand 1; TNF-α, tumour necrosis factor alpha.

Figure 2

Correlation between key analytes and clinical measurements at baseline and week 12. Line of regression and CIs are shown for CCL19 and SLEDAI-2K (A), TNF-α (B) and CXCL10 (C) and anti-dsDNA expression levels, TNFRSF9 and swollen (D) and tender (E) joint count, and between IL-6 and worst joint pain (F). CCL19, C-C motif chemokine ligand 19; CXCL10, C-X-C motif chemokine ligand 10; TNF-α, tumour necrosis factor alpha; IL-6, interleukin-6; TNFRSF9, TNF receptor superfamily member 9.