Tofacitinib benefits sustained following methotrexate withdrawal in RA

The Janus kinase inhibitor tofacitinib remained effective and safe even after discontinuing the csDMARD* methotrexate in patients with moderate-to-severe rheumatoid arthritis (RA) who achieved low disease activity (LDA) with a combination of the two drugs, the ORAL Shift** trial suggests, highlighting the feasibility of methotrexate withdrawal in this setting.

“[RA] patients receiving more than two treatments are less likely to [adhere] to methotrexate and … often discontinue at their own discretion,” said the researchers. “[Therefore, we] investigated the possibility of discontinuing methotrexate among tofacitinib-methotrexate [responders and evaluated] the efficacy and safety of tofacitinib after methotrexate withdrawal.”

Participants (n=623) received open-label tofacitinib modified-release 11 mg once daily and methotrexate for 24 weeks. Following which, those who had achieved LDA (CDAI*** ≤10; n=533) were randomized 1:1 into the double-blind phase to continue the regimen or shift to tofacitinib monotherapy for another 24 weeks. [Lancet Rheumatol 2019;1:e23-34]

Despite the increased disease activity with tofacitinib monotherapy vs tofacitinib-methotrexate from week 24–48 (DAS28-4-ESR^# mean change, 0.3 vs 0.0), the difference suggests noninferiority of the former to the latter regimen. “[This] suggests that patients who achieve LDA or remission with tofacitinib-methotrexate may consider withdrawing methotrexate without significant worsening of disease activity,” said the researchers.

Over time, DAS28-4-ESR changes remained similar between groups that by week 48, mean scores were 3.33 and 3.13 with tofacitinib monotherapy and tofacitinib-methotrexate, respectively.

The incidence of adverse events (AEs) was also similar between groups (41 percent for both). Most AEs were mild to moderate in severity, the most common being alanine aminotransferase increase and nasopharyngitis.

The addition of tofacitinib to csDMARDs has been shown to improve disease activity and inhibit progression of structural damage in individuals with inadequate response to csDMARDs. [Ann Intern Med 2013;159:253-261] A modified-release tofacitinib formulation can provide a convenient, once-daily dosing option, translating to improved drug adherence and consequently, improved disease control. [J Manag Care Pharm 2012;18:527-539]

It should be noted that the achievement of LDA was based on CDAI, while the noninferiority was based on DAS28-4-ESR. Moreover, the double-blind phase enrolled participants based on LDA at one timepoint only (week 24) and not sustained LDA. “[Therefore,] the results might not be generalized to patients who achieve LDA [beyond 24 weeks]. The 24-week duration [may have] precluded the analysis of the longer-term effect of methotrexate withdrawal on the persistence of the efficacy of tofacitinib and on radiographic progression,” noted the researchers.

The study also countered guideline recommendations of cautious tapering to avoid flares. [Arthritis Rheumatol 2016;68:1-26; www.nice.org.uk/guidance/ng100/resources/rheumatoid-arthritis-in-adultsmanagement-pdf-66141531233989, accessed 5 November 2019] “[Nonetheless,] this study answered an important clinical question because patients who are responding well will often have their methotrexate simply discontinued in real-world practice,” the investigators pointed out.

“These data are clinically meaningful as they further support the dosing and regimen options of tofacitinib … These novel findings could further inform treatment guidelines regarding optimal approaches to treatment tapering or discontinuation of methotrexate in patients with RA,” said the researchers.