Abstract
Systemic lupus erythematosus SLE is characterised by abnormalities in cellular and humoral immunity, while disturbances in cytokine production became very clear in recent years. Identification of increased IL-6, IL-17, IL-12 and IL-23, BAFF, and especially type I IFN production by different cell types, provided the rationale for targeting these cytokines and their corresponding cytokine receptors using biologics. Since these cytokine activate various intracellular pathways, such as Jak/Stat signaling, activation of the NfκB or using spleen tyrosine kinase (Syk), Bruton’s tyrosine kinase (BTK), small molecules inhibiting these pathways are being investigated in various clinical studies. It should be emphasised that most of the above mentioned intracellular pathways may vary between different immune cells and tissues and can have interactions which have not been fully delineated. However, certain strategies target multiple key pathways along with inhibiting various cytokines (multiple targeting therapy)1 which holds the promise to cover broadly heterogeneous SLE, a therapeutic principle that has already been introduced in antihypertensive and ant infectious treatment algorithms.
As a first example in patients with SLE, treatment with the Jak1/Jak2 blocking agent (jakinib) baricitinib showed improvements of skin and joint manifestations among patients with a daily dose of 4 mg/d but less pronounced under 2 mg/d in a Phase II trial over 24 weeks.2 Another Phase Ib/IIa trial using tofacitinib as Jak1/Jak3 selective inhibitor in SLE has been reported without substantial safety concerns and early signs of efficacy.3 In addition to jakinib in studies with SLE, there are also trials of inhibitors of other pathways (BTK, Syk etc.) that hold promise for a new era of more efficacious and well tolerated therapies that may address the current and substantial need for the effective treatment of SLE.
Learning objectives
Discuss the potential for novel therapeutic targets in SLE
Explain the significance of the jak pathways and current treatment developments in SLE
References
Dorner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet (London, England) 2019;393(10188):2344–58.
Wallace DJ, Furie RA, Tanaka Y, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet (London, England) 2018;392(10143):222–31.
Hasni S. A Phase 1b/2a Trial of Tofacitinib, an Oral Janus Kinase Inhibitor, in Systemic Lupus Erythematosus. 13th World Congress on SLE, San Francisco April 3rd, 2019. Oral presentation.
