Publications

Effects of Secukinumab on Synovitis and Enthesitis in Patients with Psoriatic Arthritis: 52-week Clinical and Ultrasound Results from the Randomised, Double-blind ULTIMATE Trial with Open Label Extension

Semin Arthritis Rheum 2023;63:152259

D'Agostino MA,

Carron P,

Gaillez C,

Conaghan PG,

Naredo E,

López-Rdz A,

Šenolt L,

Burgos-Vargas R,

Hanova P,

Padovano I,

Cazenave T,

Stoenoiu MS,

Backhaus M,

Mouterde G,

Bao W,

Goyanka P,

Boers M,

Schett G

This Phase 3 RCT by D’Agostino, et al. assessed the long-term effect of secukinumab to placebo at tissue level on synovitis and enthesitis, and across all PsA manifestations. They found consistent improvements in clinically and ultrasound-assessed synovitis and enthesitis.

Keywords:

• Secukinumab,
• Phase 3,
• Enthesitis

Implementation of the OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Scoring System in a Randomized Phase IIb Study of Abatacept in Psoriatic Arthritis

Rheumatology (Oxford) 2022 doi: 10.1093/rheumatology/keac073

Østergaard M,

Bird P,

Pachai C,

Du S,

Wu C,

Landis J,

Fuerst T,

Ahmad HA,

Connolly SE,

Conaghan PG

In this study abatacept 30/10 mg/kg and 10 mg/kg doses were associated with greater improvements from baseline in MRI detected synovitis and tenosynovitis, respectively, compared with placebo, confirming the clinical outcomes. Indeed, inflammatory components demonstrated the greatest change from baseline.

Keywords:

• Abatacept,
• Efficacy,
• Imaging

Response to secukinumab on synovitis using Power Doppler ultrasound in psoriatic arthritis: 12-week results from a phase III study, ULTIMATE

doi: 10.1093/rheumatology/keab628

D'Agostino MA,

Schett G,

López-Rdz A,

Šenolt L,

Fazekas K,

Burgos-Vargas R,

Maldonado-Cocco J,

Naredo E,

Carron P,

Duggan AM,

Goyanka P,

Boers M,

Gaillez C

D'Agostino, et al. aimed to evaluate whether treatment with secukinumab inhibits synovitis in patients with active PsA, as measured by PDUS. They found that secukinumab rapidly and significantly decreased synovitis, indicating a direct effect of IL-17 inhibition on the synovium in patients with PsA.

Keywords:

• IL-17,
• Secukinumab,
• Efficacy

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

Efficacy of VX-509 (decernotinib) in Combination with a Disease-modifying Antirheumatic Drug in Patients with Rheumatoid Arthritis: Clinical and MRI Findings

Ann Rheum Dis 2016;75:1979–83

Genovese M,

Yang F,

Østergaard M and Kinnman N

This Phase 2b study of VX-509 (decernotinib), a selective JAK3 inhibitor, showed that VX-509 in combination with stable DMARD therapy was effective for improving synovitis and osteitis as assessed by MRI in patients who had an inadequate response to DMARD therapy.Patients were randomised to treatment groups receiving either placebo, VX-509 100 mg, 200 mg or300 mg for 12 weeks. Minimum inclusion criteria included Grade ≥2 clinical synovitis in either the wrist or two metacarpophalangeal joints. A...

Keywords:

• JAK,
• Decernotinib

Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibition

Annals of the Rheumatic Diseases. 2015 Sep 9. doi:10.1136/annrheumdis-2014-207201

W Gao,

T McGarry,

C Orr,

J McCormick,

D J Veale,

U Fearon

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis (Ps) and characterised by synovitis and progressive destruction of articular cartilage and bone. Recently developed agents for PsA target IL12p40, IL-6 and IL-17, several of which signal through the JAK family of receptor-associated tyrosine kinases. Tofacitinib is a drug of the JAK inhibitor class and is currently approved for the treatment of RA in 27 countries. This study evaluated the effect of tofacitini...

Keywords:

• JAK,
• Tofacitinib,
• Basic Science,
• Review

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

Features of the synovium of individuals at risk of developing rheumatoid arthritis

Arthritis and Rheumatology March 2014:66;513-522

de Hair MJH,

van de Sande MGH,

Ramwadhdoebe TH et al

This study expands on previous findings that synovial inflammation does not coincide with the appearance of rheumatoid arthritis. This was a markedly larger study compared to previous, with 55 individuals assessed. All 55 subjects were positive for IgM rheumatoid factor and/or anti-citrillinated protein antibody as well as possessing no physical evidence of arthritis. 15 of the individuals tested developed arthritis after a median time of 13 months. In these patients the presence of inflammatory...

Keywords:

• Preclinical,
• MOA

Emergence of proinflammaotry autoreactive T-cell responses in preclinical rheumatoid arthritis

The Lancet, Volume 383, Page S22, 26 February 2014

Aslam A,

Nam J,

Hunt L et al

Before the onset of clinically apparent disease, the pathogenesis of RA goes through a number of sequential phases. The presence of autoimmunity through RF and ACPAs can be detected up to 13 years before the onset of clinical synovitis. An important component of the immune system is Treg cells which limit damage caused by excessive immune activity. These cells have been found to be dysfunctional in RA. This study aimed to identify autoreactive T cells to a known RA-associated antigen and determi...

Keywords:

• Preclinical,
• MOA

Physiology of cytokine pathways in rheumatoid arthritis

Arthritis Care & Research 2001; 45(1):101-6

Arend WP

This review from 2001 describes the main cytokines involved in the pathophysiology of rheumatoid synovitis, and the redundant and synergistic nature of cytokine pathways in rheumatoid arthritis (RA). The self-regulating nature of cytokines are explained through the actions of anti-inflammatory cytokines, opposing cytokines, cytokine receptor antagonists, and naturally occurring antibodies. The paper explains that as disease often results when an imbalance develops in the cytokine network, therap...

Keywords:

• JAK,
• Basic Science,
• MOA,
• Review