Graduale Riduzione versus Regime Stazionario del Methotrexate in combinazione con Tocilizumab per l’Artrite Reumatoide: un Trial Randomizzato in Doppio Cieco

Rheumatology (Oxford) 2018;57(1):84–91

Edwards CJ,

Ӧstӧr AJK,

Naisbett-Groet B,

Kiely P

Methotrexate (MTX) tapering in patients with active, severe RA receiving intravenous tocilizumab (TCZ) was non-inferior to continuing stable MTX doses in maintaining a good/moderate EULAR response. Although MTX and bDMARD combination therapy may produce better response rates than bDMARD monotherapy, one third of patients discontinue or are non-compliant with MTX due to preference or toxicity. This randomised, non-inferiority study investigated the efficacy and tolerability of MTX tapering and ma...

Danno Articolare Radiografico in Pazienti con Artrite Reumatoide Precoce: Confronto tra Strategie Treat-to-Target Basate su Tocilizumab e Methotrexate

Rheumatology (Oxford) 2017 Dec 1;56(12):2179-2189 doi: 10.1093/rheumatology/kex319

Teitsma XM,

Jacobs JWG,

Welsing PMJ,

Pethö-Schramm A,

Borm MEA,

Hendriks L,

Denissen NHAM,

van Laar JM,

Lafeber FPJG,

Bijlsma JWJ

Patient-reported outcomes (PROs) vastly improved in the first 24 weeks post-initiation of tocilizumab (TCZ) therapies compared to methotrexate (MTX) monotherapy in the U-Act-Early trial.U-Act-Early was a two-year, treat-to-target study that compared the safety and efficacy of TCZ and MTX treatment strategies in DMARD-naïve patients with early RA. Sustained remission was classed as more effective in patients given TCZ monotherapy or combination therapy with MTX compared to MTX alone. TCZ therapie...

Discontinuation of Tofacitinib after achieving Low Disease Activity in Patients with Rheumatoid Arthritis: a Multicentere, Observational Study

Rheumatology. Doi 10.1093/rheumatology/kex068

Kubo S,

Yamaoka K,

Amano K,

Nagano S,

Tohma S,

Suematsu E,

Nagasawa H,

Iwata K and Tanaka Y

This study showed that in patients who achieved low disease activity (LDA), it is possible to discontinue tofacitinib without flare in approximately one-third of patients. Patients from the tofacitinib Phase 3 programme and long-term extension study were enroled. Discontinuation was based on physician-patient decision making with informed consent. The primary endpoint was the proportion of patients who remained tofacitinib free at post-treatment Week 52. Of 64 patients treated with tofacitinib w...

Keywords:

• JAK,
• Tofacitinib,
• Real-World

Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase 2b Study in Patients with Active Rheumatoid Arthritis

Arthritis Rheumatol 2017. DOI 10.1002/art.40036.

Kremer J,

Genovese MC,

Keystone E,

Taylor PC,

Zuckerman SH,

Ruotolo G,

Schlichting DE,

Crotzer VL,

Nantz E,

Beattie SD and Macias WL

In this analysis of the effect of baricitinib on changes in lipid profile, lipoprotein particle size and apolipoprotein content, increases in serum lipids were observed with HDL-C increases correlating with improved clinical outcomes.Eligible patients (N=301) met the inclusion criteria for the Phase 2b randomised, double-blind, placebo-controlled study.1 Patients were assigned in a 2:1:1:1:1 ratio to once-daily doses of placebo or baricitinib 1, 2, 4, or 8 mg, respectively. Those receiving 2 mg,...

Keywords:

• JAK,
• Baricitinib,
• Phase 2

Baricitinib in Patients with Refractory Rheumatoid Arthritis

N Engl J Med. 2016 Mar 31;374(13):1243-52. doi: 10.1056/NEJMoa1507247

Genovese et al.

For patients who have an inadequate response or unacceptable side effects associated with biologic DMARDs, the options for treatment beyond conventional DMARDs are limited. This phase 3 trial of the JAK 1/2 inhibitor, baricitinib, studied its efficacy in bDMARD-IR patients. 527 patients were randomized to either baricitinib 2mg, 4mg or placebo for up to 24 weeks. At week 12 the primary endpoints were tested hierarchically to control type 1 error; these endpoints were ACR20, HAQ-DI score, DAS28-C...

Keywords:

• JAK,
• Baricitinib,
• Review

Clinical Relevance of VPAC1 Receptor Expression in Early Arthritis: Association with IL-6 and Disease Activity

 PLoS ONE 11(2): e0149141. doi:10.1371/journal. pone.0149141

Seoane I,

Ortiz A,

Piris L et al

VPAC1 and VPAC2 both mediate anti-inflammatory and immunoregulatory responses in RA. Both these are receptors of vasoactive intestinal peptide (VIP), a broadly distributed peptide found in neural, endocrine and immune cells, which triggers biological response when interacting with the aforementioned receptors. It has recently been described in Martinez et al. that those patients with low levels of VIP have worse disease outcome.1This study analyzed 250 blood samples from the Princesa early Arthr...

Keywords:

• Basic Science,
• Review

Impact of obesity on the clinical outcome of rheumatologic patients in biotherapy

Autoimmunity Reviews Doi: 10.1016/j.autrev.2016.01.010

Iannone et al

Obesity is increasingly becoming a public health concern as its prevalence continues to grow in the United States and Western nations. Obesity has been shown to be an inflammatory condition that impacts multiple tissues and systems, including the immune system possibly linking to rheumatic diseases. In this review, Iannone et al overview the epidemiology and clinical outcomes of PsA and/or RA patients with comorbid obesity.Large cohort and prospective studies in Italy, the US, and the UK have s...

Keywords:

• ACR

Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial

Arthritis Res Ther. 2015 Apr 6;17(1):95.

Kremer JM,

Kivitz AJ,

Simon-Campos JA,

Nasonov EL,

Tony HP,

Lee SK,

Vlahos B,

Hammond C,

Bukowski J,

Li H,

Schulman SL,

Raber S,

Zuckerman A,

Isaacs JD

Mean increases from baseline in patient serum creatinine (SCr) levels have been observed in the clinical development programme for the JAK inhibitor tofacitinib. These increases predominantly occurred within the first three months, and reversed with tofacitinib withdrawal.

This phase 1, randomised, placebo-controlled, parallel-group, 2-period study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib, relative to placebo, in 148 patients with active RA. Result...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Renal

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

Structural basis for the recognition of interferon-α receptor by tyrosine kinase 2

Nat Struct Mol Biol. 2014 May;21(5):443-8. doi: 10.1038/nsmb.2807. Epub 2014 Apr 6

Wallweber HJA,

Tam C,

Franke Y et al

Janus kinases, JAKs, are essential in the mediation of cytokine and interferon signalling whilst also being crucial to body processes such as immune function, hematopoeises, metabolism and cellular growth. However, it is not known is how the four members of the JAK family interact with and are activated by over 30 cytokine receptors with near perfect affinity and specificity. Currently, there are no crystal structures available for any JAK bound to a cytokine receptor. This study sought address ...

Keywords:

• TYK2,
• Preclinical,
• MOA