Janus kinase inhibitors in autoimmune diseases

O’Shea, John J.; Kontzias, Apostolos; Yamaoka, Kunihiro; Tanaka, Yoshiya; Laurence, Arian

doi:10.1136/annrheumdis-2012-202576

Cited by 381 publications

(314 citation statements)

References 47 publications

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“…Proinflammatory cytokines implicated in the pathogenesis of rheumatoid arthritis (RA), including interleukin (IL) 6, IL-15, IL-17, IL-23, interferon-a/β, interferon-g, and granulocyte-macrophage colony stimulating factor 1,2 , primarily act through intracellular Janus kinase (JAK) signaling pathways 3 . Drugs that inhibit these pathways 3,4 , which may directly block cytokine signaling or indirectly modulate T cell functions through suppression of CD80/86 expression in dendritic cells 5 , are currently the focus of extensive development efforts for RA.…”

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confidence: 99%

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Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study

Tanaka

Emoto²,

Chen³

et al. 2016

J Rheumatol

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115

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Objective.To evaluate efficacy and safety, baricitinib [Janus kinase (JAK) 1/JAK2 inhibitor] was compared with placebo in Japanese patients with active rheumatoid arthritis (RA) despite background treatment with methotrexate (MTX).Methods.This was a phase IIB, double-blind, randomized, placebo-controlled study (clinicaltrials.gov: NCT01469013). Patients had moderate to severe active adult-onset RA despite stable treatment with MTX. Patients (n = 145) were randomized in a 2:1:1:1:1 ratio to placebo or 1 mg, 2 mg, 4 mg, or 8 mg oral baricitinib daily for 12 weeks. The primary analysis compared the combined 4/8-mg dose groups with placebo for the American College of Rheumatology (ACR) 20 response rate at 12 weeks. Other outcomes included additional measures of disease activity, physical function, laboratory abnormalities, and adverse events.Results.A significantly higher proportion of patients in the combined 4/8-mg baricitinib group (37/48, 77%) compared with the placebo group (15/49, 31%) had at least an ACR20 response after 12 weeks of treatment (p < 0.001). Significant improvements in disease activity, remission, and physical function were observed as early as Week 2 of treatment with baricitinib, particularly with daily doses of ≥ 4 mg. Only 1 patient receiving baricitinib discontinued because of an adverse event. Adverse event rates with baricitinib doses ≤ 4 mg daily were similar to placebo, but there was a higher incidence of adverse events and laboratory abnormalities in the 8-mg group.Conclusion.In this phase II study, baricitinib was well tolerated and rapidly improved the signs, symptoms, and physical function of Japanese patients with active RA, supporting continued development of baricitinib (clinicaltrials.govNCT01469013).

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“…Drugs that inhibit these pathways 3,4 , which may directly block cytokine signaling or indirectly modulate T cell functions through suppression of CD80/86 expression in dendritic cells 5 , are currently the focus of extensive development efforts for RA. Baricitinib is a potent, selective, orally administered, reversible inhibitor of JAK signaling 6 .…”

mentioning

confidence: 99%

Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study

Tanaka

Emoto²,

Chen³

et al. 2016

J Rheumatol

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115

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“…Several proinflammatory cytokines including interleukin 6 (IL-6), IL-12, IL-23, interferon, granulocytemacrophage colony-stimulating factor, and the γ chain cytokines including IL-2 use the Janus kinase (JAK) intracellular signaling pathway and have been associated with RA. Several small-molecule JAK inhibitors are in clinical development, each having a particular selectivity for inhibition of 1 or more of the 4 enzymes within the JAK family 1 .…”

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confidence: 99%

Safety and Efficacy of Baricitinib Through 128 Weeks in an Open-label, Longterm Extension Study in Patients with Rheumatoid Arthritis

Keystone

Genovese²,

Schlichting³

et al. 2017

J Rheumatol

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Objective.To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353).Methods.After a 24-week blinded period, eligible patients entered an initial 52-week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when ≥ 6 tender and ≥ 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose.Results.In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment-emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128.Conclusion.In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE.

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“…Due to this, and additional inhibition of the action of IFN, there is markedly increased the risk of cancer. 7 However, a meta-analysis showed that risk of infection with both JAK inhibitors and biological therapy is more or less the same. 16 Toafacitinib can additionally cause adverse effects like urinary tract infection, diarrhea, nasopharyngitis and upper respiratory infections.…”

Section: Adverse Effectsmentioning

confidence: 99%

“…Hence inhibiting these enzymes interrupts the signal transduction that results from the interaction of cytokines with their receptors. 6,7 …”

Section: Introductionmentioning

confidence: 99%

A novel approach in treatment of rheumatoid arthritis: Janus kinase inhibitors

Bhanwra

Ahluwalia

2015

Int J Basic Clin Pharmacol

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Janus kinase inhibitors in autoimmune diseases

Cited by 381 publications

References 47 publications

Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study

Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study

Safety and Efficacy of Baricitinib Through 128 Weeks in an Open-label, Longterm Extension Study in Patients with Rheumatoid Arthritis

A novel approach in treatment of rheumatoid arthritis: Janus kinase inhibitors

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