Publications

Phase 2 trial of deucravacitinib in psoriatic arthritis: Biomarkers associated with disease activity, pharmacodynamics, and clinical responses

Arthritis Rheumatol 2024 doi: 10.1002/art.42921 Epub ahead of print

FitzGerald O,

Gladman DD,

Mease PJ,

Ritchlin C,

Smolen JS,

Gao L,

Hu Y,

Nowak M,

Banerjee S,

Catlett I

FitzGerald, et al. found that Deucravacitinib significantly impacted biomarkers associated with TYK2 signalling pathways of key inflammatory cytokines, including IL-23 and Type I IFN, and those related to collagen matrix turnover.

Keywords:

• Deucravacitinib,
• Phase 2,
• PK/PD

Modulation of IL-23 Signalling with Guselkumab in Biologic-Naïve Patients Versus TNF Inhibitor-Inadequate Responders with Active Psoriatic Arthritis

Arthritis Rheumatol 2024 doi 10.1002/art.42803 Epub ahead of print

Siebert S,

Coates LC,

Schett G,

Raychaudhuri SP,

Chen W,

Gao S,

Seridi L,

Chakravarty SD,

Shawi M,

Lavie F,

Sharaf M,

Zimmermann M,

Kollmeier AP,

Xu XL,

Rahman P,

Mease PJ,

Deodhar A

Guselkumab treatment exhibited generally comparable and significant pharmacodynamic effects on IL-23/Th17–associated cytokines across participants with PsA who are biologic-naïve or have TNFi-IR. In coming to this conclusion, investigators assessed and compared immunologic differences and associations with clinical response to guselkumab in participants with active PsA who were biologic-naïve or TNFi-IR.

Keywords:

• Basic Science,
• Guselkumab

Two Phase 3 Trials of Baricitinib for Alopecia Areata

N Engl J Med. 2022. Epub ahead of print doi: 10.1056/NEJMoa2110343

King B,

Ohyama M,

Kwon O,

Zlotogorski A,

Ko J,

Mesinkovska NA,

Hordinsky M,

Dutronc Y,

Wu WS,

McCollam J,

Chiasserini C,

Yu G,

Stanley S,

Holzwarth K,

DeLozier AM,

Sinclair R,

BRAVE-AA Investigators

Phase 3 trials in patients with severe alopecia areata show that baricitinib is superior to placebo with respect to hair regrowth at 36 weeks.
Alopecia areata is characterised by nonscarring hair loss that can affect any hair-bearing site. Although mild cases of this emotionally- and psychosocially-distressing autoimmune disease may resolve within 12 months, more severe forms of the disease are unlikely to remit without treatment.

Keywords:

• JAK,
• Baricitinib,
• Phase 3

Highlights of 2021

Please click the links below to go to the CSF review of each paper

McInnes IB

I’m sure we’d all hoped that this year would be a return to normal but, in the midst of the challenges we’ve faced with COVID-19, the rheumatology community has continued to deliver excellent publications, and we’ve covered many of these on the CSF. Here are my highlights from 2021's publications: Points to Consider for the Treatment of Immune-Mediated Inflammatory Diseases With Janus Kinase Inhibitors: A Co...

Keywords:

• Review

A review of JAK-STAT signalling in the pathogenesis of spondyloarthritis and the role of JAK inhibition

Rheumatology (Oxford). 2021. Epub ahead of print. doi: 10.1093/rheumatology/keab740.

McInnes IB,

Szekanecz Z,

McGonagle D,

Maksymowych WP,

Pfeil A,

Lippe R,

Song IH,

Lertratanakul A,

Sornasse T,

Biljan A,

Deodhar A

JAK inhibitors are likely to become an important part of the overall treatment paradigm for spondyloarthritis (SpA).Although not fully understood, the pathogenesis of SpA is complex and thought to involve both environmental and genetic factors that together elicit a chronic inflammatory response involving the innate and adaptive immune systems. Several different cytokines, TNF, IL-17A, IL-12/23 and IL-23, which are directly/indirectly affected by JAK molecules, are involved in the pathogenesis o...

Keywords:

• JAK,
• Basic Science,
• Review

JAK/STAT pathway and nociceptive cytokine signalling in rheumatoid arthritis and psoriatic arthritis

Clin Exp Rheumatol. 2021;39(3):668-675.

Crispino N,

Ciccia F.

The JAK/STAT pathway is receiving increasing attention in modulation of nociceptive responses, given its clear role in cytokine signalling. The authors of this review speculate that JAKinibs may have an effect on the modulation of nociception and reduction of pain.Crispino N, et al. review the impact of pain in patients with rheumatic disease and the physiological basis of modulating nociceptive pain. They examine the role of cytokines in the modulation of pain and analyse current clinical JAKin...

Keywords:

• JAK,
• Basic Science,
• MOA

JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib

Ann Rheum Dis. 2021 Mar 19:annrheumdis-2020-219012. Epub ahead of print. DOI: 10.1136/annrheumdis-2020-219012

Traves PG,

Murray B,

Campigotto F,

Galien R,

Meng A,

Di Paolo JA

The first study to combine in vitro inhibition of cytokine responses in whole blood with clinical pharmacokinetics of individual JAKinibs to model daily cytokine-mediated pharmacodynamic profiles in healthy individuals and patients with RA, has demonstrated that JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type.Traves and colleagues have observed that JAKinibs have unique, differential effects on specific cytokine signalling pathways, dependent on cytokine stimulus, ST...

Keywords:

• JAK,
• Basic Science,
• MOA

Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity

PLoS ONE 2021;16(1):e0244187

Ptacek J,

Hawtin RE,

Sun D,

Louie B,

Evensen E,

Mittleman BB,

Cesano A,

Cavet G,

Bingham CO III,

Cofield SS,

Curtis JR,

Danila MI,

Raman C,

Furie RA,

Genovese MC,

et al

This analysis provides evidence that immune cell signalling pathways are important in RA. There were consistent differences between RA patients and healthy controls in IFNα, IL-6, IL-10 and GM-CSF+ IL-2 induced JAK/STAT signalling in multiple immune cell subsets.We know that RA is characterised by dysregulation of immune responses, but the exact cause is unknown. Recently, single-cell transcriptomics and mass cytometry confirmed the critical role of activated immune cells and fibroblasts, increa...

Keywords:

• JAK,
• Basic Science

The JAK/STAT Pathway: A Focus on Pain in Rheumatoid Arthritis

Semin Arthritis Rheum. 2021 Feb;51(1):278-284

Simon LS,

Taylor PC,

Choy EH,

Sebba A,

Quebe A,

Knopp KL,

Porreca F

Many cytokines associated with RA pathogenesis and pain are affected directly or indirectly by the JAK/STAT pathway, therapeutic targeting may offer promise. Having better understanding of these mechanisms can help clinicians make treatment decisions that optimise the control of inflammation and pain. However, pain in patients with RA is complex and involves multiple driving mechanisms that may differentially occur over time in different people. Although one known constant is that nociceptive ac...

Keywords:

• JAK,
• Basic Science,
• Review

Highlights of 2020

Please click the links below to go to the CSF review of each paper

McInnes. I

2020 unfolded apace, dominated by COVID-19 - we have all had to adapt in our practice and in our knowledge base. Amid this there have continued to be a constant flow of publications and science in cytokine signaling, and as in previous years as we come the end of 2020, I will highlight some of the notable papers of the year. You can find the most notable papers, as selected by CSF Steering Committee Chair Professor Iain McInnes, with links to their respective detailed summaries below:

Keywords:

• Review