Systemic Lupus Erythematosus
A Phase 1b/2a Trial of Tofacitinib, an Oral Janus Kinase Inhibitor, in Systemic Lupus Erythematosus
Sarfaraz Hasni, MD
National Institute of Arthritis, Musculoskeletal, and Skin diseases/ National Institutes of Health, Bethesda, MD, USA
Tofacitinib has been studied in SLE in a small phase 1b/2a trial.
Tofacitinib was well tolerated, abrogated the type I interferon (IFN) gene signature, and improved endothelial dysfunction.
Many key cytokines implicated in the pathogenesis of systemic lupus erythematosus (SLE) are dependent on activation of Janus kinases (JAKs) for intracellular signaling. For this reason, JAK inhibitors are of interest in treatment of SLE. A double-blind, randomized, placebo-controlled, phase 2 trial has been carried out investigating oral tofacitinib in patients with active SLE despite standard of care. 
Investigate the safety and tolerability of tofacitinib in active SLE.
Type of study, patients, and inclusion criteria
Phase 1b/2a trial in 30 patients with mild to moderate SLE assigned to tofacitinib (n=20) or placebo (n=10).
The STAT4 risk allele was present/absent in a 1:1 ratio in randomized patients.
Tofacitinib was given at 5 mg twice daily for 56 days followed by 28 days off study drug.
The primary objective was to assess the safety and tolerability of tofacitinib in SLE.
In the tofacitinib group, 74% of patients experienced a mild adverse event and 26% a moderate adverse event, compared to 82% and 11% in the placebo group, respectively.
Most of the adverse events with tofacitinib were mild infections; there were no opportunistic infections and no thrombo-embolic events.
Tofacitinib led to significant inhibition of pSTAT1 in CD4+ T cells.
Tofacitinib also abrogated the type I IFN gene signature.
Tofacitinib decreased arterial stiffness as measured by pulse wave velocity.
The JAK inhibitor led to a significant increase in HDL cholesterol by day 56, with no changes in LDL cholesterol or triglycerides.
There was a significant increase in HDL particle size with tofacitinib at day 56.
Tofacitinib was well tolerated, and abrogated the type I IFN gene signature.
It also improved endothelial dysfunction, and increased the HDL cholesterol level and function, particularly in patients with the STAT4 risk allele.
Long-term studies are warranted in order to understand the efficacy of tofacitinib in SLE and any potential impact on prevention of cardiovascular disease.
Key messages/Clinical perspectives
JAK inhibition is a potentially new and promising therapy for SLE, although additional studies are needed.
Presenter disclosure: The presenter has reported relationships with AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Glaxo Smith and Klein, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB.
Written by: Patrick Moore, PhD
Reviewed by: Alessia Alunno, MD, PhD
Local reviewers: Alessia Alunno, MD, PhD (Italian); Aurélie Najm, MD (French); Yukinori Okada, MD, PhD (Japanese); Fabian Proft, MD (German); Javier Rodríguez-Carrio, MSc, PhD (Spanish); Priscilla Wong, MD (Chinese)
Scientific Editor: Leonard H. Calabrese, DO