Publications

Secukinumab in Plaque Psoriasis — Results of Two Phase 3 Trials

N Engl J Med. 2014;371(4):326–338.

Langley RG,

Elewski BE,

Lebwohl M,

et al.

Secukinumab is a fully human monoclonal antibody that selectively binds to and neutralises interleukin-17A, a cytokine shown to play a crucial role in plaque psoriasis, as well as other immune-mediated diseases.

These two pivotal phase 3 studies in plaque psoriasis, FIXTURE and ERAUSRE, were sponsored by Novartis Pharmaceuticals. Secukinumab met all primary endpoints, PASI 75 response and the response of 0 or 1 on the modified investigator’s global assessment, as well as key secondary end...

Keywords:

• IL-17,
• Secukinumab,
• Phase 3

Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials

Arthritis Res Ther. 2014;16(4):R158

Isaacs JD,

Zuckerman A,

Krishnaswami S,

et al.

Despite preclinical and healthy volunteer studies of tofacitinib showing no evidence of nephrotoxicity, increases in mean serum creatinine levels have been observed in patients treated with the drug during the RA clinical development programme. This report explores the clinical significance of this change.

Serum creatinine values and renal adverse event data were pooled from patients who received =1 dose of tofacitinib either with background DMARDs or as monotherapy in five Phase 3 studie...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Renal

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

Cohen S,

Radominski SC,

Gomez-Reino JJ,

et al.

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...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Phase 3,
• LTE,
• Mortality,
• Infections

Herpes Zoster and Tofacitinib Therapy in Patients with Rheumatoid Arthritis

Arthritis Rheumatol. 2014 Jun 18. [Epub ahead of print]

Winthrop KL,

Yamanaka H,

Valdez H,

et al.

It is well established that patients with RA are at an increased risk of herpes zoster (HZ). What is less well known is whether some of the newer therapies available for treatment of RA increase this risk. Tofacitinib has been reported to be associated with an increased risk of HZ and this study quantifies that risk and reviews potential factors that represent an increased risk. Using data from the tofacitinib RA development programme; phase 2, 3, and long-term extension clinical trials, over 20...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Infections

Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation

Nature. 2014;510(7503):157–161.

Riol-Blanco L,

Ordovas-Montanes J,

Perro M,

et al.

The abnormal activation of skin immune cells, such as dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, by IL-23 is known to provoke psoriasis-type inflammation. What is less well known is how peripheral nerves regulate cutaneous immune responses. In this study, IL-23-dependent psoriasis-like inflammation was induced in mice to help determine the precise molecular mechanism of neuroimmune communication in the skin. Findings indicate nocic...

Keywords:

• Preclinical,
• MOA

JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T cells and Th17 cells

J Immunol 2014; 192:4417-4424

Park JS,

Lee J,

Lim MA et al

In this study, Park et al sought to investigate the effects of the JAK2 inhibitor, AG490 in RA. Using murine CIA models, both preventative and therapeutic models were investigated. In the preventative model, CIA mice treated with AG490 showed a significantly lower incidence rate of arthritis and arthritic scores when compared to mice injected with vehicle. In the therapeutic model, as in the preventative, AG490 treated mice exhibited less severe arthritis. Through further experiments, it was dem...

Keywords:

• JAK,
• Preclinical,
• MOA

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

Wollenhaupt J,

SIlverfield J,

Lee Eb et al

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...

Keywords:

• JAK,
• Tofacitinib,
• Phase 3,
• LTE

Blocking the janus-activated kinase pathway reduces tumor necrosis factor alpha-induced interlukin-18 bioactivity by caspase-1 inhibition

Arthritis Research and Therapy 2014,16:R102

Marotte H,

Tsou PS,

Fedorova T et al

IL-18, a member of the IL-1 family, has been shown to play an important role in immune response and is involved in the pathogenesis of RA. The study objective was to examine the role of the JAK pathway in modulating TNFa-induced-IL18 bioactivity by reducing caspase-1 function. Caspase-1 is the protease that cleaves pro-IL-18 to IL-18, thereby activating it. In testing it was noted that by blocking the JAK pathway significantly decreased caspase-1 transcription, expression and activity showing th...

Keywords:

• JAK,
• Preclinical,
• MOA

Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants

Ann Rheum Dis Published Online First 24 April 2014 doi:10.1136/annrheumdis-2013-204143

Hartkamp LM,

Fine JS,

van Es IE et al

Bruton’s tyrosine kinase, a downstream target of PI3K signalling, has been shown to be crucial in the B lymphocyte and myeloid cell contribution to murine models of arthritis. Synovial tissue samples were taken from biologically naïve RA (n=16) and PsA (n=12) patients in order to assess the expression of BTK. Separate RA synovial explants (n=8) were used to assess the effects of the specific BTK inhibitor RN486. BTK was expressed at equivalent levels in both RA and PsA synovial tissue, however e...

Keywords:

• BTK,
• Preclinical,
• MOA

What is the future of targeted therapy in rheumatology: biologics or small molecules?

BMC Medicine 2014, 12:43

Moscai A,

Kovace L and Gergely P

Our understanding of inflammatory rheumatic diseases such as rheumatoid arthritis has significantly increased over the last 20 years. With this greater understanding we have seen a significant improvement in the therapy of RA and other inflammatory rheumatic diseases. In this review, Moscai et al. discuss the improvements in therapies for the treatment of these diseases from the introduction of methotrexate as a frontline therapy through to the current era and approval of the first small molecul...

Keywords:

• Review