Publications

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

Baricitinib Inhibits Structural Joint Damage Progression in Patients with Rheumatoid Arthritis – A Comprehensive Review

Arthritis Res Ther 2021;23(1):3.

Emery P,

Durez P,

Hueber AJ,

Ide la Torre I,

Larsson E,

Holzkämper T,

Tanaka Y

MRI studies have shown that BARI reduces joint inflammation and damage in patients with moderate-to-severe active RA. This review summarises the effects of BARI on structural joint damage progression and the mechanisms underlying these effects, using MRI data from across the clinical trial program. Early preclinical animal models showed a significant reduction in joint inflammation, ankle width, and bone resorption. Efficacy and safety of BARI have been confirmed in an extensive programme, inclu...

Keywords:

• JAK,
• Baricitinib,
• Radiographic,
• 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

Efficacy of Baricitinib in Treating Rheumatoid Arthritis: Modulatory Effects on Fibrotic and Inflammatory Biomarkers in a Real-Life Setting

Int Immunopharmacol. 2020 Sep;86:106748.

Alessandro M,

Perillo F,

Refini R,

Bergantini L,

Bellisai F,

Selvi E,

Cameli P,

Manganelli S,

Conticini E,

Cantarini L,

Sestini P,

Frediani B,

Bargagli E

BARI demonstrated to be a safe immune modulator that reduces the concentrations biomarkers of lung fibrosis and inflammation in RA patients, including a subgroup with interstitial lung involvement. Professor Alessandro and colleagues analysed the effects of baricitinib in a population of RA and RA-ILD patients in a real-life setting, describing any changes in lung function parameters, serum inflammatory biomarkers and fibrotic biomarkers after 6 months of treatment. Fifteen patients were recruit...

Keywords:

• JAK,
• Baricitinib,
• Basic Science,
• Biomarkers

Assessment of the association of baseline anti-CarbV and anti-MCV antibodies with response to treatment and radiographic progression in an RA population treated with either methotrexate or baricitinib: post-hoc analyses from RA-BEGIN

Arthritis Res Ther. 2020;22(1):193

López-Romero P,

Martinez-Gamboa L,

Bang H,

de la Torre I,

Holzkämper T,

Feist E

Autoantibodies associated with the onset of RA have gained attention in recent years as prognostic biomarkers. Though not used diagnostically, anti-CarbV (carbamylated vimentin) and anti-MCV (vimentin modified by citrullination) baseline titers are being investigated as predictors of treatment response. In this post-hoc analysis of data from the RA-BEGIN cohort of active RA patients, López-Romero and colleagues consider the potential predictive values of baseline anti-CarbV and anti-MCV titers r...

Keywords:

• JAK,
• Baricitinib,
• Efficacy,
• Bone,
• Radiographic

Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double-Blind, Phase II Trial (ANDES Study)

Arthritis Rheumatol. 2020 Sep; 72(9): 1435–1446.

Cohen S,

Tuckwell K,

Katsumoto TR,

Zhao R,

Galanter J,

Lee C,

Rae J,

Toth B,

Ramamoorthi N,

Hackney JA,

Berman A,

Damjanov N,

Fedkov D,

Jeka S,

Chinn LW,

Townsend MJ,

Morimoto AM,

Genovese MC

In this randomised phase II trial with MTX treatment-refractory RA patients, greater efficacy was observed with fenebrutinib 150 mg once daily or 200 mg twice daily compared to placebo, while response rates were numerically similar to those observed with adalimumab. BTK inhibitors have demonstrated clinical efficacy in B cell malignancies and multiple sclerosis, although there is limited clinical evidence of its efficacy in RA. Fenebrutinib (FEN) an orally active and selective non-covalent inhib...

Keywords:

• BTK,
• Fenebrutinib,
• Phase 2

Filgotinib, a JAK1 Inhibitor, Modulates Disease Related Biomarkers in Rheumatoid Arthritis: Results from Two Randomized, Controlled Phase 2b Trials

Rheumatol Ther. 2020 DOI: 10.1007/s40744-019-00192-5

Tarrant JM,

Galien R,

Wanying L,

Goyal L,

Pan Y,

Hawtin R,

Zhang W,

Van der Aa A and Taylor PC

In this study examining the effect of FIL on a panel of biomarkers, FIL down-modulated several key inflammatory mediators of signalling pathways in RA - independent of MTX background therapy. This confirmed the strong network effects of the JAK1 node in autoimmunity, matrix and cartilage degradation, angiogenesis, and leukocyte adhesion and recruitment. Biomarkers key to RA pathophysiology were measured at baseline, Wk4 and Wk12 in FIL 100 mg, FIL 200 mg or PBO treatment groups from two phase 2b...

Keywords:

• JAK,
• Filgotinib,
• Phase 2,
• MOA,
• Biomarkers

Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective Janus kinase 1 Inhibitor, after Short-term Treatment of Rheumatoid Arthritis: Results of Two randomized Phase IIA Trials

Arthritis Rheumatol. 2017 Oct;69(10):1949-1959. doi: 10.1002/art.40186

Vanhoutte F,

Mazur M,

Voloshyn O,

Stanislavchuk M,

Van der Aa A,

Namour F,

Galien R,

Meuleners L,

van ‘t Klooster G

In two 4-week exploratory Phase 2a trials in MTX-inadequate responder (IR) patients with RA, the highly selective JAK1 inhibitor filgotinib met the primary endpoint of ACR20 at Week 4, showing greater response than placebo.Study 1, a proof-of-concept study, included 127 patients randomised to placebo, filgotinib 100 mg BID or filgotinib 200 mg QD. Study 2, was a dose-ranging study and included 91 patients randomised to placebo, filgotinib 30 mg QD, filgotinib 75 mg QD, filgotinib 150 mg QD or fi...

Keywords:

• JAK,
• Filgotinib,
• Phase 2,
• PK/PD

Early changes in blood-based joint tissue destruction biomarkers are predictive of response to tocilizumab in the LITHE study

Arthritis Research & Therapy (2016) 18:13 DOI: 10.1186/s13075-015-0913-x

Bay-Jensen A,

Platt A,

Siebuhr A,

Christiansen C,

Byrjalsen I,

Karsdal M

One of the major challenges of RA treatment is choosing the correct treatment and dose for the individual patient, as treatment response can be heterogeneous. To help select the appropriate treatment, there is a need for effective and non-invasive ways to monitor disease activity and progression. In the LITHE study, Bay-Jensen et al. investigate whether early biomarker measurements could predict early joint protection response to TCZ. The biomarkers (CRPM, VICM, C1M, C2M, C3M, and CTX-I/OC [bone...

Keywords:

• IL-6,
• Tocilizumab,
• Biomarkers

The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis

Ann Rheum Dis. 2014 Nov 14. pii: annrheumdis-2014-206028. doi: 10.1136/annrheumdis-2014-206028. [Epub ahead of print]

Boyle DL,

Soma K,

Hodge J,

Kavanaugh A,

Mandel D,

Mease P,

Shurmur R,

Singhal AK,

Wei N,

Rosengren S,

Kaplan I,

Krishnaswami S,

Luo Z,

Bradley J,

Firestein GS

Targeting intracellular pathways such as JAK/STAT represents a novel approach to the treatment of RA. Tofacitinib is an oral JAK inhibitor, proven to be effective in the treatment of RA, yet the pathways affected by tofacitinib and the effects on gene expression in situ are unknown. In this study, Boyle et al. tested the hypothesis that tofacitinib targets cytokine signalling critical to the pathogenesis of rheumatoid synovitis by investigating tofacitinib effects on synovial pathobiology.

Keywords:

• JAK,
• Tofacitinib,
• Phase 1,
• MOA