The Jakinibs in systemic lupus erythematosus: progress and prospects

ABSTRACT

Introduction: Multiple pathways are involved in the pathogenesis of systemic lupus erythematosus (SLE). The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway mediates the intracellular signals of more than 60 cytokines, growth factors and hormones from the type I/II cytokine receptors. Dysregulation of the cytokines is a hallmark of SLE; inhibition of downstream signaling mediated by the JAKs is an attractive therapeutic option.

Areas covered: This article reviews the preliminary data concerning the efficacy of the JAK inhibitors (Jakinibs) in SLE. JAK inhibition has shown promise in murine lupus dermatitis and nephritis. Ex-vivo studies of human SLE have demonstrated the effect of JAK1/2 inhibition on the activation of the STAT proteins and autoantibody production from B cells. A Phase II trial reported modest efficacy of baricitinib in improving synovitis in SLE patients.

Expert opinions: Inhibition of the JAK-STAT pathway is an attractive therapeutic option. The convenience of oral administration and lower production cost of the Jakinibs could replace the biological agents in the treatment hierarchy of autoimmune inflammatory diseases. Additional clinical data are needed; results of ongoing studies of the newer Jakinibs in cutaneous and non-life-threatening lupus are eagerly awaited.

KEYWORDS:

• JAK
• Jakinib
• lupus
• targeted
• therapeutic
• systemic lupus
• SLE
• autoimmune disease

Article highlights

• Dysregulation of the cytokines is a hallmark of SLE. Targeting the downstream signaling pathways mediated by the JAK-STAT proteins allows simultaneous suppression of multiple cytokines and is therefore an attractive therapeutic option for SLE.

• JAK2/3 inhibition has shown promise in murine lupus nephritis and dermatitis.

• Ex-vivo studies from human SLE also demonstrated effect of JAK1/2 inhibition on activation of the STAT proteins and autoantibody production from B cells.

• A Phase II randomized controlled trial reported modest efficacy of a JAK1/2 inhibitor, baricitinib, in ameliorating lupus arthritis.

• Newer Jakinibs are being tested in cutaneous and systemic manifestations of SLE.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has served as an advisor or consultant for AstraZeneca, MedImmune, Bristol-Myers Squibb, GlaxoSmithKline and Biogen Idec. Other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.