In the Journals

Patients with low-disease RA on tofacitinib, methotrexate can safely withdraw methotrexate

Stanley Cohen, MD
Stanley B. Cohen

Patients with rheumatoid arthritis who achieve low disease activity with tofacitinib plus methotrexate can safely withdraw methotrexate without fear of worsening disease activity, according to findings published in The Lancet Rheumatology.

“Previous studies had demonstrated greater efficacy with TNF inhibitors in combination with conventional synthetic DMARDs in comparison to monotherapy,” Stanley B. Cohen, MD, of the Metroplex Clinical Research Center and the University of Texas Southwestern Medical Center, told Healio Rheumatology. “Part of this enhanced improvement may be due to the reduction in anti-drug antibodies in patients receiving methotrexate. Methotrexate withdrawal studies with tocilizumab and etanercept had suggested patients in low disease activity in general maintain benefit after methotrexate withdrawal.”

“Additionally, observational registries have demonstrated that approximately 30% of patients on biologics take these as monotherapy due to their desire not to take multiple therapies or due to aggravating side effects from conventional synthetic DMARDs,” he added. “Therefore, it was deemed important to determine the benefit of tofacitinib monotherapy in those patients who might withdraw methotrexate after achieving disease control.”

To analyze the efficacy and safety of tofacitinib (Xeljanz, Pfizer) following methotrexate withdrawal among patients with RA who achieve low disease activity with a combination of the two drugs, Cohen and colleagues conducted the phase 3b/4 ORAL Shift study. According to the researchers, the noninferiority trial, conducted in 109 centers across 16 countries, recruited adults with moderate-to-severe RA and an inadequate response to methotrexate.

For the open-label phase, 694 patients were enrolled between Sept. 1, 2016, and Nov. 1, 2017, with 623 receiving study treatment for 24 weeks. That treatment included 11 mg of modified-release tofacitinib once daily plus methotrexate.

After 24 weeks, the 533 patients who achieved low disease activity — defined as a clinical disease activity index 10 or less — were randomly assigned to receive tofacitinib plus placebo or continue tofacitinib plus methotrexate for another 24 weeks. Among these participants, 267 were assigned to the tofacitinib monotherapy group while 266 continued with the combination therapy. The primary endpoint was the least squares mean change from week 24 to week 48 in disease activity score in 28 joints with four variables, including erythrocyte sedimentation rate (DAS28-4[ESR]).

Cohen and colleagues conducted their primary analysis in all participants who received at least one dose of study treatment in both phases, whereas safety was assessed in both phases in all patients who received at least one dose of study treatment since enrollment. Three patients in the monotherapy group failed to initiate treatment, and were not included in the primary analysis. Tofacitinib monotherapy was declared noninferior to combination therapy with methotrexate if the upper bound of the 95% CI for the difference in change in DAS28-4(ESR) between treatment groups was less than 0.6.

According to the researchers, tofacitinib demonstrated noninferiority compared with combination therapy with methotrexate, with a difference of 0.3 (95% CI, 0.12-0.48). The proportion of patients who experienced adverse events was 41% in both the monotherapy and combination therapy groups. In addition, five patients from each group discontinued treatment due of adverse events, and two patients in the combination therapy group died. The researchers reported no new safety findings up to 48 weeks.

“This data demonstrates that in patients with low disease activity who desire to discontinue methotrexate 80% or greater will maintain benefit over 24 months,” Cohen said. “The obvious limitation of this trial is the lack of longer-term follow-up to determine persistence of response and impact on radiographic progression. However, since these small molecules don't induce anti-drug antibodies as seen with monoclonal antibodies it is possible that persistence of benefit could be maintained for longer duration.” – by Jason Laday

Disclosure: Cohen reports having served as a consultant and investigator for AbbVie, Eli Lilly, Genentech, Gilead and Pfizer. Please see the full study for additional authors’ disclosures.

Stanley Cohen, MD
Stanley B. Cohen

Patients with rheumatoid arthritis who achieve low disease activity with tofacitinib plus methotrexate can safely withdraw methotrexate without fear of worsening disease activity, according to findings published in The Lancet Rheumatology.

“Previous studies had demonstrated greater efficacy with TNF inhibitors in combination with conventional synthetic DMARDs in comparison to monotherapy,” Stanley B. Cohen, MD, of the Metroplex Clinical Research Center and the University of Texas Southwestern Medical Center, told Healio Rheumatology. “Part of this enhanced improvement may be due to the reduction in anti-drug antibodies in patients receiving methotrexate. Methotrexate withdrawal studies with tocilizumab and etanercept had suggested patients in low disease activity in general maintain benefit after methotrexate withdrawal.”

“Additionally, observational registries have demonstrated that approximately 30% of patients on biologics take these as monotherapy due to their desire not to take multiple therapies or due to aggravating side effects from conventional synthetic DMARDs,” he added. “Therefore, it was deemed important to determine the benefit of tofacitinib monotherapy in those patients who might withdraw methotrexate after achieving disease control.”

To analyze the efficacy and safety of tofacitinib (Xeljanz, Pfizer) following methotrexate withdrawal among patients with RA who achieve low disease activity with a combination of the two drugs, Cohen and colleagues conducted the phase 3b/4 ORAL Shift study. According to the researchers, the noninferiority trial, conducted in 109 centers across 16 countries, recruited adults with moderate-to-severe RA and an inadequate response to methotrexate.

For the open-label phase, 694 patients were enrolled between Sept. 1, 2016, and Nov. 1, 2017, with 623 receiving study treatment for 24 weeks. That treatment included 11 mg of modified-release tofacitinib once daily plus methotrexate.

After 24 weeks, the 533 patients who achieved low disease activity — defined as a clinical disease activity index 10 or less — were randomly assigned to receive tofacitinib plus placebo or continue tofacitinib plus methotrexate for another 24 weeks. Among these participants, 267 were assigned to the tofacitinib monotherapy group while 266 continued with the combination therapy. The primary endpoint was the least squares mean change from week 24 to week 48 in disease activity score in 28 joints with four variables, including erythrocyte sedimentation rate (DAS28-4[ESR]).

Cohen and colleagues conducted their primary analysis in all participants who received at least one dose of study treatment in both phases, whereas safety was assessed in both phases in all patients who received at least one dose of study treatment since enrollment. Three patients in the monotherapy group failed to initiate treatment, and were not included in the primary analysis. Tofacitinib monotherapy was declared noninferior to combination therapy with methotrexate if the upper bound of the 95% CI for the difference in change in DAS28-4(ESR) between treatment groups was less than 0.6.

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According to the researchers, tofacitinib demonstrated noninferiority compared with combination therapy with methotrexate, with a difference of 0.3 (95% CI, 0.12-0.48). The proportion of patients who experienced adverse events was 41% in both the monotherapy and combination therapy groups. In addition, five patients from each group discontinued treatment due of adverse events, and two patients in the combination therapy group died. The researchers reported no new safety findings up to 48 weeks.

“This data demonstrates that in patients with low disease activity who desire to discontinue methotrexate 80% or greater will maintain benefit over 24 months,” Cohen said. “The obvious limitation of this trial is the lack of longer-term follow-up to determine persistence of response and impact on radiographic progression. However, since these small molecules don't induce anti-drug antibodies as seen with monoclonal antibodies it is possible that persistence of benefit could be maintained for longer duration.” – by Jason Laday

Disclosure: Cohen reports having served as a consultant and investigator for AbbVie, Eli Lilly, Genentech, Gilead and Pfizer. Please see the full study for additional authors’ disclosures.