Following non-response by rheumatoid arthritis patients to the standard anti-rheumatic agent methotrexate, instead of a combined treatment of methotrexate and a biologic agent, a study has identified an equally effective oral treatment option: the combination of methotrexate and the chemically synthesised tofacitinib.
Patients suffering from rheumatoid arthritis are treated for around six months with the standard anti-rheumatic agent methotrexate, to which many patients respond very well. However, if they do not respond and no remission or at least reduction in the activity of the disease can be achieved, they are given a combined treatment of methotrexate and a biologic agent (frequently an anti-TNF, such as adalimumab, administered by injection), if risk factors are present.
An international research group has now shown that there is another, equally effective oral treatment option: the combination of methotrexate and the chemically synthesised Janus Kinase Inhibitor, tofacitinib. MedUni Vienna rheumatologist Josef Smolen was senior author of the study
Smolen, head of the division of rheumatology at MedUni Vienna and the third most quoted rheumatology expert, and researchers from the US, Argentina, Australia, the UK and China, were able to demonstrate that the combination of methotrexate/tofacitinib produced equally effective results as the current standard combination of methotrexate/adalimumab. The latter has to be injected into patients every two weeks, whereas the new option involves taking two tablets a day – a potential advantage for patients.
A total of just over 1,100 volunteers were involved in the study.
Says Smolen: "At the same time we were able to show that monotherapy with tofacitinib does not achieve such good results as combined therapy with methotrexate, even though it is still quite effective."
How does Tofacitinib work? It inhibits particular enzymes (Janus Kinases (JAK)), which are jointly responsible for the inflammatory response in rheumatoid arthritis. JAKs carry signals from various inflammatory messenger substances, such as interleukin-6 or interferons, into the cell and are therefore largely responsible for triggering the destructive inflammation that occurs in rheumatoid arthritis. If these enzymes are inhibited, the painful immune response that occurs in this autoimmune disease is suppressed. Tofacitinib, which has already been on the market in the US for some time now, was recently licensed in the EU.
Summary
Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate.
Methods: ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than −13·0%.
Findings: 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI −6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (−6 [−14 to 3]) or tofacitinib and methotrexate (−8 [−16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year.
Interpretation: Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination.
Authors
Roy Fleischmann, Eduardo Mysler, Stephen Hall, Alan J Kivitz, Robert J Moots, Zhen Luo, Ryan DeMasi, Koshika Soma, Richard Zhang, Liza Takiya, Svitlana Tatulych, Christopher Mojcik, Sriram Krishnaswami, Sujatha Menon, Josef S Smolen
[link url="https://www.meduniwien.ac.at/web/en/about-us/news/detailseite/2017/news-im-juni-2017/new-oral-treatment-option-for-rheumatoid-arthritis/"]Medical University of Vienna material[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31618-5/fulltext"]The Lancet article summary[/link]