June 2013

Cytokines in the pathogenesis of rheumatoid arthritis

Nature Reviews Immunology 2007; 7:429-42

The imbalance between the activity of pro- and anti-inflammatory cytokines favouring induction of autoimmunity, chronic inflammation and joint damage is well known, but how cytokines are organised within a hierarchical regulatory network and which cytokines are the best targets for clinical intervention is uncertain. This review therefore examines the effector function of cytokines in the immunological processes central to the pathogenesis of rheumatoid arthritis (RA). The paper aims to try and ...

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Small molecules targeting JAKs—a new approach in the treatment of rheumatoid arthritis

Rheumatology 2013: doi: 10.1093/rheumatology/kes417

This article focuses on the development of new small molecular inhibitors of Janus kinases (Jaks) in clinical trials for rheumatoid arthritis (RA). Of these, tofacitinib is at the most advanced stage of its clinical development and this article includes an overview of the results from the main tofacitinib clinical trials to date. These include the ORAL-Start study in methotrexate (MTX)-naïve patients; ORAL-Scan in inadequate responders to MTX; ORAL-Solo and ORAL-Sync in inadequate responders to ...

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Back to the future: oral targeted therapy for RA and other autoimmune diseases

Nature Reviews Rheumatology 2013; 9(3):173-82

This review paper considers how advances in understanding of the disease process underlying rheumatoid arthritis (RA) and the development of novel techniques have transformed the management of this progressively disabling condition. Physicians are no longer limited to prescribing symptomatic treatments such as non-steroidal anti-inflammatory drugs (NSAIDs) or choosing from a seemingly random array of drugs drawn from multiple disciplines, such as methotrexate and sulphasalazine, which are descri...

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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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An Oral Spleen Tyrosine Kinase (Syk) Inhibitor for Rheumatoid Arthritis

The New England Journal of Medicine 2010; 363(14):1303-12

This is the first phase 2 study to be published for spleen tyrosine kinase (Syk) inhibitor R788 (fostamatinib). This phase 2 study ingestigated the efficacy and safety of fostamatinib in patients with active RA despite long-term treatment with methotrexate. In this 6-month, double-blind, placebo-controlled trial, patients were randomised to receive two doses of R788 (100 mg twice daily or 150 mg once daily) or placebo once or twice daily. Significantly more patients on R788 achieved ACR 20 respo...

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An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents

Arthritis & Rheumatism 2011; 63(2):337-45

This was the first phase 2 study to be published investigating the efficacy and safety of the spleen kinase (Syk) inhibitor R788 (fostamatinib) in patients with refractory rheumatoid arthritis (RA). In this multicentre, randomised, double-blind, placebo-controlled, 3-month trial, patients with active RA on stable background treatment (excluding biologics) were randomised to receive 100 mg R788 or placebo twice daily. Differences in ACR20 responses were significant at week 6 (p=0.003), but not th...

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A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone

Arthritis & Rheumatism 2012; 64(4):970-81

This study was one of two 24-week, phase 2b studies undertaken to characterise the efficacy and safety dose-response profile of the oral Janus kinase (JAK) inhibitor tofacitinib. Six doses of tofacitinib (20 mg daily and 1, 3, 5, 10 and 15 mg twice daily) and placebo were compared as add-on therapy in adults with active RA despite methotrexate (MTX) therapy. At week 12, ACR 20 response rates were significantly higher with all tofacitinib doses than with placebo (tofacitinib 45.7–58.1%; 33% place...

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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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