January 2014

Emerging cell and cytokine targets in rheumatoid arthritis

Nat Rev Rheumatol. 2013. doi:10.1038/nrrheum.2013.168

Despite major progress in the treatment of RA over the past decade, sustained clinical remission remains elusive. The identification of new treatment targets is therefore necessary, with much research currently being undertaken in this area. Novel therapeutic approaches currently being investigated include T cell-directed therapies targeting both T cell activation and regulation; and the targeting of pathogenic B cell functions, including the use of depleting and non-depleting B cell-directed an...

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October 2013

Ibrutinib and novel BTK inhibitors in clinical development

Journal of Hematology & Oncology 2013;6:59

Bruton’s tyrosine kinase (BTK) is a part of the cytokine signalling pathways involved in malignancies and autoimmune disorders.. Akinleye et al. provide a review of all the current BTK inhibitors in preclinical and clinical trials for B-cell malignancies and autoimmune disorders, including rheumatoid arthritis. Particular focus is placed on ibrutinib, a novel human BTK-inhibitor, currently in phase III clinical trials. The authors also discuss four new compounds with potential indications in rh...

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August 2013

Safety profile of protein kinase inhibitors in rheumatoid arthritis: a systematic review and meta-analysis

Ann Rheum Dis April 2013; doi:10.1136/annrheumdis-2012-203116

Salgado and colleagues conducted a systematic literature review of the safety profiles of protein kinase inhibitors (PKis) used for the treatment of rheumatoid arthritis (RA). Additionally, the study aims included identification of any class and molecule-related target and off-target adverse events. Data from 11,858 patients across 41 publications (phase 2 and 3 studies and two pooled analyses) were analysed. As well as published trials of PKi in RA, studies on healthy individuals and patients w...

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Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives

Pharmacol Ther. 2013 May; 138(2):294–309

This review focuses on targeting spleen tyrosine kinase (SYK) and Bruton’s tyrosine kinase (BTK) inhibitors as potential immunomodulatory agents for the treatment of autoimmune and inflammatory disorders with SYK inhibition showing encouraging efficacy in patients with RA. The paper describes the role of SYK and BTK in several therapy areas including autoimmune diseases, allergic inflammatory disorders and haematological cancers as well as their role in innate immunity and regulators of adaptive...

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June 2013

Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease

Molecular Immunology 2007; 44:2497-506

This review from 2007 provides an overview of the largest cytokine receptor family, the haematopoietin receptors, as well as other key components involved in one of the major cytokine signalling pathways implicated in autoimmune and inflammatory diseases. This includes the Janus kinases (Jaks), signal transducers and activators of transcription (Stats) and suppressors of cytokine signalling genes (Socs). Essentially, when a cytokine binds to a receptor from this group a functional cytokine recep...

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Janus kinases in immune cell signaling

Immunological Reviews 2009; 228:273-87

This review from 2009 describes the Janus Kinases (JAK) that includes JAK1, JAK2, and JAK3, a subgroup of non-receptor protein tyrosine kinases. This protein family has a diverse range of functions including roles in cell growth, survival, development, and differentiation of a variety of cells, and especially immune and haematopoietic cells. Current knowledge of protein structure, regulatory mechanisms, signalling pathways and intracellular interactions for the JAK family is reviewed. The paper ...

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Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor

Clinical Immunology 2007; 124:244-57

This study investigated the capacity of the novel oral spleen tyrosine kinase (Syk) inhibitor R406, and its prodrug R788 (fostamatinib), to suppress the reversed passive Arthrus reaction (RPA) and collagen-induced arthritis (CIA) in rats. R406 (0.1, 1, 5 and 10 mg/kg) and R788 (10 and 30 mg/kg) reduced the cutaneous RPA reaction and inflammatory oedema in a dose-dependent manner, with statistically significant reductions in extravascular leakage and tissue swelling (72% reduction with R406 10 mg...

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Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050

Journal of Immunology 2010; 184(9):5298-307

This preclinical characterisation study examined the efficacy and tolerability of the small molecule INCB028050 (now known as baricitinib), an orally bioavailable, selective Janus kinase (JAK) 1/JAK2 inhibitor, in rodent models of arthritis. The decision to investigate its effects of INCB028050 followed positive evidence for the related compound ruxolitinib, the JAK inhibitor tofacitinib and the IL-6 inhibitor tocilizumab in rheumatoid arthritis (RA). In this preclinical study, INCB028050 was sh...

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Tofacitinib or adalimumab versus placebo in rheumatoid arthritis

The New England Journal of Medicine 2012; 367(6):508-19

The ORAL Standard trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 12-month, phase 3 study compared the efficacy of tofacitinib with the TNF inhibitor adalimumab or placebo. Patients with active RA despite background methotrexate (MTX) were randomised to 5 or 10 mg tofacitinib twice daily, 40 mg adalimumab fortnightly, or placebo, which was switched to tofacitinib at month 3 in non-responders and month 6 f...

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Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial

The Lancet 2013; 381(9865):451-60

The ORAL Step trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 6-month, double-blind, parallel-group phase 3 study investigated the efficacy and safety of tofacitinib in adults with moderate to severe rheumatoid arthritis (RA) with an inadequate response to tumour necrosis factor (TNF) inhibitors. Patients were randomised to 5 or 10 mg tofacitinib twice daily or placebo, which was switched to tofacitinib a...

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