Baricitinib, a Janus kinase (JAK)1/JAK2 inhibitor, improved disease activity in systemic lupus erythematosus (SLE) adults receiving standard background therapy in a phase 2 trial (NCT02708095).1 The aim of this study was to elucidate the mechanism of action of baricitinib in SLE.
Patients with SLE were treated with baricitinib-2mg or -4mg in a phase 2, randomized, placebo-controlled study. Sera from 68 patients (baricitinib-2mg: n=29; baricitinib-4mg: n=25; placebo: n=14) were collected at baseline and Week 12 and analyzed for cytokines using a Proximity Extension Assay (PEA) with 87 detectable analytes (Target 96 Inflammation Panel (Olink)). Interferon (IFN) scores were determined using a Modaplex assay. Spearman correlations were computed. Analyte changes from baseline at Week 12 were compared between baricitinib-4mg and placebo groups by Wilcoxon rank-sum or t-tests. Adjusted p<0.05 was considered significant.
At baseline, CXCL10 (r=0.50), CXCL11 (r=0.38), and CCL19 (r=0.45) correlated with the IFN signature. Confirming previous findings using Quanterix assays2, PEA analysis indicated that baricitinib-4mg, but not placebo, reduced IL-6 and IL-12p40 in SLE. Additionally, baricitinib-4mg significantly downregulated 1) serum cytokines that mediate lymphocyte and monocyte/macrophage recruitment (CCL19, TNFRSF9, TNF-β/Lymphotoxin-α), and 2) cytokines that induce bone turnover and augment joint pain (TRANCE/RANKL and Artemin).
These results suggest that downregulation of key cytokines that have proinflammatory and/or regulatory functions may play a role in the mechanism by which baricitinib acts to improve SLE disease activity.
References
1) Wallace DJ, et al. Lancet. 2018;392(10143):222-31.
2) Dörner T, et al. Lupus Sci Med. 2020;7(1).