Baricitinib for systemic lupus erythematosus

doi:10.1016/S0140-6736(18)32763-6

The Lancet

Volume 393, Issue 10170, 2–8 February 2019, Page 402

https://doi.org/10.1016/S0140-6736(18)32763-6 Get rights and content

References (4)

DJ Wallace et al.
Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial
Lancet
(2018)
A Mullard
FDA approves Eli Lilly's baricitinib
Nat Rev Drug Discov
(2018)

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Systemic Autoinflammatory Diseases: A Growing Family of Disorders of Overlapping Immune Dysfunction
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IL-1 inhibition in more complex disorders exemplifies this concept with the recognition of the central role of inflammasomes and the IL-1 family of cytokines in disorders, such as sJIA, gout, Behçet disease, macrophage activation syndrome, and cytokine storm syndromes.4,58 The discovery that polygenic autoimmune disorders (e.g., systemic lupus erythematosus [SLE]) feature type I IFN overactivation has triggered the investigation of IFN inhibition in their treatment.59 In addition, the localized manifestations of SAIDs involving dysregulation of the IL-1 family in diseases, such as deficiency of IL-1 receptor antagonist (DIRA), deficiency of IL-36 receptor antagonist (DITRA), Majeed syndrome, and CARD 14–mediated pustular psoriasis (CAMPS), also have provided important insights into the role of those mediators in the homeostasis of local tissues (e.g., keratinocytes and epithelia),25 and, remarkably, the discovery of IL-1 dysregulation in atherosclerosis has triggered investigations of the role of IL-1 in cardiovascular diseases.42
Current and future status of JAK inhibitors
2021, The Lancet
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Serious adverse events were seen in 9·6% of patients in the baricitinib 4 mg group versus 4·8% in the placebo group. As raised by Yuan and colleagues70 in response to the study, the 4 mg dosing strategy of baricitinib was not approved by the FDA for rheumatoid arthritis due to safety concerns of potential infectious and thrombotic complications, hence additional follow-up and more knowledge are required for this dosing regimen. Two dosing strata are being explored in the phase 3 trial, BRAVE II, with an ongoing long-term follow-up study from the earlier trials (SLE-BRAVE-X; NCT03843125).
An enhanced understanding of the importance of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signalling in multiple disease states has led to an increasing applicability of therapeutic intervention with JAK inhibitors. These agents have revolutionised treatments for a heterogeneous group of disorders, such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven dermatological diseases, exemplifying rapid bench-to-bedside translation. In this Therapeutics paper, we summarise the currently available data concerning the successes and safety of an array of JAK inhibitors and hypothesise on how these fields could develop.
Janus kinases (JAKs): The efficient therapeutic targets for autoimmune diseases and myeloproliferative disorders
2020, European Journal of Medicinal Chemistry
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There were also no notable safety concerns and the predefined secondary endpoints of SLE Responder Index-4 response, Lupus Low Disease Activity Score and flares of any severity were significantly improved in the Baricitinib 4 mg group versus the placebo group. This first trial and the positive findings indicate that 3 could be a favorable drug for SLE [77]. 3 is also applied for the treatment of Atopic Dermatitis (AD) which is the most common chronic inflammatory skin disease.
The Janus kinases or JAKs are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of autoimmune diseases and myeloproliferative disorders. JAKs are activated upon ligand induced receptor homo- or heterodimerization, which results in the immediate phosphorylation of tyrosine residues and the phosphotyrosines then serve as docking sites for cytoplasmic signal transducer and activator of transcription (STAT) proteins which become phosphorylated by the JAKs upon recruitment to the receptor complex. The phosphorylated STAT proteins dimerize and travel to the cellular nucleus, where they act as transcription factors. Interfering in the JAK-STAT pathway has yielded the only approved small molecule kinase inhibitors for immunological indications. Numerous medicinal chemistry studies are currently aimed at the design of novel and potent inhibitors for JAKs. Additionally, whether the second-generation inhibitors which possessed selectivity for JAKs are more efficient are under research. This Perspective summarizes the progress in the discovery and development of JAKs inhibitors, including the potential binding site and approaches for identifying small-molecule inhibitors, as well as future therapeutic perspectives in autoimmune diseases and myeloproliferative disorders are also put forward in order to provide reference and rational for the drug discovery of novel and potent JAKs inhibitors.
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Biological therapy in systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren’s syndrome: evidence- and practice-based guidance
2023, Frontiers in Immunology
Potential Drugs for the Treatment of COVID-19: Synthesis, Brief History and Application
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CorrespondenceBaricitinib for systemic lupus erythematosus

Lancet

FDA approves Eli Lilly's baricitinib

Nat Rev Drug Discov

Correspondence
Baricitinib for systemic lupus erythematosus