Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction

Abstract

Objectives Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. To date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a Janus kinase (JAK) inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and on its associated vascular pathology remains to be characterized. Methods MRL/lpr lupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular trap (NET) release, endothelium-dependent vasorelaxation and endothelial differentiation were compared in treated and untreated mice. Results Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated NET formation and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective as both preventive and therapeutic strategies. Conclusions Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage.

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

“…Consistent with this amelioration in lupus phenotype, LA1 treatment resulted in significant amelioration in levels of serum anti-dsDNA antibodies and total IgG, various inflammatory cytokines and chemokines, and spleen weight, in comparison with vehicle-treated mice ( Figure 5, F-H), which correlates with reduced inflammation in LA1-treated mice. While the differences in numbers of splenic double-negative T cells (not shown), activated T and B cells, or plasma cells, DCs, macrophages, and neutrophils did not achieve statistical significance between LA1-treated and vehicle-treated mice (Supplemental Figures 12 and 13), the trends showed decreases in splenic macrophages, activated B cells, and plasma cells, which may explain the differences in autoantibody synthesis, as previously described (54,55). To investigate whether the efficacy of LA1 in vivo was associated with modulation of the IFN-I pathway, we isolated mRNA from MRL/Lpr splenocytes and quantified relative expression of several candidate genes.…”

Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

“…For SLE, preclinical studies have been encouraging 109 . A Phase 1 tofacitinib trial (NCT02535689) and a Phase 2 baricitinib study (NCT02708095) are currently recruiting patients.…”

“…Moreover, tofacitinib reduces cholesterol ester catabolism, which is elevated in RA patients 148 . Tofacitinib also reduces arterial stiffness 149 and lupus-associated vascular dysfunction 109 . Long-term data from Phase IV clinical trials is needed to determine whether JAK inhibition ultimately prevents, ameliorates, or exacerbates CV risk.…”

Using regulatory genomics data to interpret the function of disease variants and prioritise genes from expression studies

“…Tofacitinib, a pan-JAK inhibitor, showed promising results in mouse 58 and is currently being tested or safety in a phase I clinical trial. We find 7 GWAS SNPs that are blood eQTLs linked to the expression of C2, a protease active in the complement signalling cascade.…”