October 2015

Comparison of the efficacies of abatacept and tocilizumab in patients with rheumatoid arthritis by propensity score matching

Annals of the Rheumatic Diseases. 2015 Aug 5. doi:pii: annrheumdis-2015-207784. 10.1136/annrheumdis-2015-207784. [Epub ahead of print]

This study compared the clinical outcomes at one year after the treatment either abatacept or tocilizumab in routine clinical practice. This study employed propensity score matching and demonstrated that abatacept and tocilizumab had comparable continuing efficacies, and that treatment with the drugs resulted in comparable clinical and functional remission rates. Additionally, abatacept and tocilizumab showed similar effectiveness with or without MTX.While clinical efficacies, including SDAI, w...

January 2015

Potential Mechanisms Leading to the Abnormal Lipid Profile in Patients With Rheumatoid Arthritis Versus Healthy Volunteers and Reversal by Tofacitinib

Arthritis Rheumatol. 2015;67(3):616-25.

Active RA is associated with changes in both high- and low-density lipoprotein cholesterol as well as changes in the level and function of several HDL-associated proteins, yet the pathways and mechanisms involved with systemic inflammation altered lipid metabolism have not been determined. In addition, treatments for active RA are known to modify lipid metabolism, such as increasing circulating cholesterol levels. In the clinical development programme, a proportion of tofacitinib-treated patien...

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Efficacy and Safety of Tofacitinib as Monotherapy in Japanese Patients With Active Rheumatoid Arthritis: A 12-Week, Randomized, Phase 2 Study

Mod Rheumatol. 2014 Dec 11:1–25. [Epub ahead of print]

In Japan, the biologic DMARDs infliximab, etanercept, adalimumab, golimumab and certolizumab pegol, as well as tocilizumab and abatacept are approved for use in patients with active RA and an inadequate response to existing therapies. However, not all patients respond to these therapies adequately, creating an unmet need for therapeutic options with alternative mechanisms of action.

The oral JAK inhibitor tofacitinib has demonstrated efficacy as monotherapy or in combination with DMARDs ...

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IL-6 stimulates intestinal epithelial proliferation and repair after injury

PLoS One. 2014 Dec 5;9(12):e114195. doi: 10.1371/journal.pone.0114195. eCollection 2014.

IL-6 is an inflammatory cytokine known to contribute to a number of autoimmune diseases such as RA. Therapies targeting the soluble IL-6 receptor have now become effective treatments for RA. However, one unforeseen, yet rare, potential complication of anti-IL-6 therapy is bowel perforation. Yet within the intestine, IL-6 protects intestinal epithelial cells from apoptosis during prolonged inflammation.

The authors hypothesized that IL-6 may have beneficial properties in wound response/rep...

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December 2014

The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels

Rheumatology (Oxford). 2014 Nov 17. pii: keu430. [Epub ahead of print]

Non-response, parenteral administration and cost to produce are all aspects associated with the currently available anti-cytokine agents for RA. These related factors mean that alternative drugs are now being developed. Recent developments in therapeutic drugs to treat RA have focused on Janus kinases (JAKs) and signal transducer and activator of transcription (STATs) transcription pathways. Several cytokines that regulate immune responses in RA, such as IFN-g, IL-6 and IL-10, activate JAK-STAT ...

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August 2014

Analysis of Infections and All-Cause Mortality in Phase II, III and Long-Term Extension Studies of Tofacitinib in Patients with Rheumatoid Arthritis

Arthritis Rheumatol. 2014;66(11):2924–2937

This study pools data from the global tofacitinib RA development programme (phase II, phase III and long-term extension studies) to determine the rate of infections and all-cause mortality with tofacitinib treatment. In total, 4,789 patients within these studies received tofacitinib, at varying doses and with varying duration.

The overall incidence rate of serious infections was 3.09 events/100 patient-years (95% CI 2.73–3.49), which was stable over time, with pneumonia and skin and soft...

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June 2014

Alternative p38 MAPKs Are Essential for Collagen-Induced Arthritis

Arthritis and Rheumatology Vol66, No. 5, May2014 pp 1208-1217

MAPK family proteins are regulatory proteins, affecting processes such as synthesis and release of proinflammatory molecules which contribute to the pathogenesis of RA. In particular, the p38 MAPK protein family is central to proinflammatory cytokine production. There are four member of the p38 group; p38α, p38β, p38γ and p38δ. This study sought to evaluate p38γ and p38δ deficiency in mice CIA model. In p38γ-/- or p38δ-/- mice, the percentage of mic...

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Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor

Science 344, 2014; doi: 10.1126/science.1249783

Class I cytokine receptors are key regulators of many processes within the body. The receptors use the JAK-STAT signalling pathway, the deregulation of which causes it to become an important pathway in oncogenesis. Despite this, the processes responsible for JAK2 activation by class I receptors remains elusive. Previous studies using growth hormone and its receptor have led to a model of receptor activation where hormone induced receptor dimerization resulted in close proximity of the receptor i...

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May 2014

Safety and Efficacy of Tofacitinib, an Oral Janus Kinse Inhibitor, for the Treatment of Rheumatoid Arthritis, in Open-Label Longterm Extension Studies

J Rheumatol 2014;41;837-852

This study pooled data from two LTE studies involving patients who had previously participated in qualifying phase I, II and III studies. Data up to 60 months was included for safety aspects and efficacy data up to 48 months. However data for 10 mg BID and tofacitinib monotherapy was limited after 24 and 36 months respectively. Over the two studies, 4102 patients were treated for a total of 5963 patient years.Herpes zoster, both serious and non-serious, had a higher incidence rate in tofacitinib...

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April 2014

Molecular pathways: Molecular basis for sensitivity and resistance to JAK inhibitors

Clin Cancer Research doi:10.1158/1078-0432.CCR-13-0279

Janus kinases (JAKs) mediate the regulation of a variety of cytokine signals with alterations in JAK1, JAK2, JAK3 and Tyk2 signalling contributing to many disease states including autoimmune diseases and haematological malignancies. Recently tofacitinib and ruxolitinib have been approved for treatment for rheumatoid arthritis and myelofibrosis respectively. Several JAK2 inhibitors, such as momelotinib and pacritinib, currently in development for myelofibrosis and the JAK1/2 inhibitor baricitinib...

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