OK to Withdraw Methotrexate Post Tofacitinib Combo Treatment

Rheumatoid arthritis patients who achieve low disease activity with a combination of tofacitinib and methotrexate, should be able to discontinue methotrexate safely and without significant worsening of disease activity, especially if they are having trouble tolerating it, new research shows.

The study, led Stanley B. Cohen, M.D., Metroplex Clinical Research Center, Dallas, was published Sept. 1 in The Lancet Rheumatology.

This is the first global study of the modified-release version of the JAK inhibitor tofacitinib, prescribed here as an 11 mg once-daily treatment. The study, which is called ORAL Shift, is also the first-known non-inferiority global clinical trial whose aim was to assess efficacy and safety of a JAK inhibitor after methotrexate withdrawal in  rheumatoid arthritis patients who have achieved low disease activity with tofacitinib and methotrexate combination treatment.

The question in this study was whether methotrexate could be safely removed from the course of treatment.

FROM THE STUDY

This was a 24-week open label phase 3b/4 non-inferiority clinical trial of rheumatoid arthritis patients from 109 treatment centers in 16 countries. It included 694 patients in the open-label phase and of these, 623 received tofacitinib modified-release 11 mg once daily plus methotrexate for 24 weeks.

The results:

• By week 24,533 (77%) of the 694 patients achieved low disease activity defined as CDAI ≤10.

• Of these, 267 were assigned to the tofacitinib monotherapy group and 266 were assigned to the tofacitinib plus methotrexate group.

• At week 48, 522 achieved low disease activity

• In terms of adverse events, 107 (41%) of 264 patients in the tofacitinib monotherapy group and 109 (41%) of 266 in the tofacitinib plus methotrexate group had adverse events of which five patients from each group discontinued treatment because of adverse events.

SIGNIFICANCE

“Most patients with rheumatoid arthritis with moderate-to-high disease activity who received tofacitinib plus methotrexate and achieved low disease activity and who cannot tolerate or prefer not to use methotrexate can consider discontinuing it without significant worsening of disease activity or unexpected safety issues,” the authors wrote.
While methotrexate is considered first-line therapy for rheumatoid arthritis, it is often ineffective by itself and is associated with tolerability issues and adverse events. It is recommended by the American College of Rheumatology and the European League Against Rheumatism that, when methotrexate treatment fails in rheumatoid arthritis, a biologic disease modifying ant-rheumatic drug such as a Janus kinase inhibitor should be started.

It has been shown that tofacitinib monotherapy is effective for the treatment of rheumatoid arthritis in patients who have never taken methotrexate, however, it was previously unknown if discontinuing methotrexate while on combination therapy with tofacitinib was safe and effective.

The results of this study indicate that withdrawal of methotrexate and continuation of tofacitinib as monotherapy in moderate to severe rheumatoid arthritis after achieving low disease activity was not inferior to staying on both drugs with regards to efficacy.

“These data are clinically meaningful as they further support the dosing and regimen options of tofacitinib treatment for managing patients with rheumatoid arthritis. Furthermore, they may be used to inform treatment guidelines regarding optimal approaches to treatment tapering or discontinuation of methotrexate in patients with rheumatoid arthritis,” the authors wrote.

Writing in a commentary that accompanied the study in The Lancet Rheumatology, Maxime Dougados, M.D., of Cochin Hospital, Paris, writes that in daily practice, adherence to methotrexate is generally low to begin with.

Dr. Dougados agrees this new study will allow patients and clinicians to discuss discontinuing methotrexate but cautions that longer-term studies will need to look at efficacy over time.

REFERENCE

Stanley B Cohen, Janet Pope, Boulos Haraoui, et al. “Methotrexate withdrawal in patients with rheumatoid arthritis who achieve low disease activity with tofacitinib modified-release 11 mg once daily plus methotrexate (ORAL Shift): a randomised, phase 3b/4, non-inferiority trial.”The Lancet Rheumatology.  Vol 1, Issue 1, PE4-E5, September 01, 2019.

Maxime Dougados. “Effective JAK inhibitor therapy in rheumatoid arthritis: can methotrexate be discontinued?” The Lancet Rheumatology.  Vol 1, Issue 1, PE4-E5, September 01, 2019.

DISCLOSURES

This study was funded by Pfizer.