July 2014

Herpes Zoster and Tofacitinib Therapy in Patients with Rheumatoid Arthritis

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

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...

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Tofacitinib Versus Methotrexate In Rheumatoid Arthritis

N Engl J Med. 2014;370(25):2377–2386.

ORAL Start is the latest trial to be reported in the tofacitinib clinical development programme. It compares the use of tofacitinib monotherapy to MTX monotherapy, in RA patients who have had either no or a sub-therapeutic dose of MTX in the past. Nine hundred and fifty eight patients received either tofacitinib (5 mg or 10 mg) twice daily, or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks. The co primary efficacy endpoints were ACR 70 response, and mean c...

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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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February 2014

Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis

Ann Rheum Dis doi:10.1136/annrheumdis-2013-204588

Systematic literature reviews were undertaken to assess the efficacy of csDMARDs, glucocorticoids and tofacitinib in the treatment of RA. The first two were updates to reviews conducted for the 2010 recommendations while the tofacitinib SLR was a complete review.Two studies identified by the csDMARD SLR, tREACH and TEAR, compared efficacy between MTX mono- and combination therapy (MTX+SSZ+HQ). Both of these studies found there was no benefit to immediate triple therapy.Further studies analysing ...

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Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis

Ann Rheum Dis doi:10.1136/annrheumdis-2013-204575

Two systematic literature reviews were undertaken to update the safety findings on synthetic and biological DMARDs in order to inform the updates to the EULAR recommendations to the treatment of RA. Of 10,559 articles screened, 49 were included for review covering a diverse range of outcomes. In the main these showed the patients on bDMARDs had a significantly greater risk of serious infections and tuberculosis compared with csDMARDs, while differences in data between studies mean a slight incre...

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Effects of tofacitinib on lymphocytes in rheumatoid arthritis: relation to efficacy and infectious adverse events

Rheumatology doi:10.1093/rheumatology/ket466

Due to its function as a JAK1/3 inhibitor, tofacitinib has effects on a wide ranging variety of cells. The authors of this paper have previously reported a suppression in cytokine production by CD4+ T lymphocytes caused by tofacitinib, while others have reported reduced chemokine production from fibroblast-like synoviocytes. The effects of tofacitinib on other cells however remain largely unknown. This study focused on tofacitinib’s effects on CD4+ T lymphocyte proliferation and on subsets of ly...

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October 2013

A meta-analysis of p38 mitogen-activated protein kinase inhibitors in patients with active rheumatoid arthritis

Clinical Rheumatology 2013 doi 10.1007/s10067-013-2340-1

The role of p38-MAPK inhibitors in treating RA is the subject of some debate. Li et al. therefore performed the first meta-analysis of the current data to evaluate the efficacy and safety of these compounds. The authors identified 3 papers, covering 4 RCTs, for analysis and the results showed that p38-MAPK inhibition achieves a better level of ACR20 improvement vs. placebo, but showed no meaningful difference in ACR50, DAS28 or CRP levels past week 12. Due to the inadequate number and quality of...

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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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The JAK inhibitor tofacitinib for active rheumatoid arthritis: results from phase III trials

International Journal of Clinical Rheumatology June 2013; 8(3):311–13

The tofacitinib ORAL research program involves six phase 3 trials (Standard, Solo, Step, Scan, Sync and Start) to assess the safety and efficacy of tofacitinib 5 and 10 mg twice daily as monotherapy, or with either background MTX or traditional DMARD therapy. This report by Salgado et al. provides an overall analysis of the each of the study designs and the clinical results to date. The results show that tofacitinib effectively controlled the signs and symptoms of RA across a range of patient po...

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June 2013

Intracellular Signal Pathways: Potential for Therapies

Current Rheumatology Reports 2009; 11:378-85

With recent progress in the development of drugs targeting signalling pathways for rheumatoid arthritis, this review article from the National Institutes of Health (NIH) provides an overview of the key intracellular pathways involved in the pathogenesis of rheumatoid arthritis. This paper also discusses some of the limitations of current drug targets including lack of clinical efficacy, potential adverse effects and cost, and highlights important issues associated with the design of target drugs...

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