Etanercept does better than methotrexate at keeping RA in remission

Rheumatoid arthritis (RA) patients achieving remission with the combination of methotrexate plus etanercept may be able to maintain their status by stopping the former and continuing treatment with the latter, as shown in the SEAM-RA* trial. In the maintenance setting, etanercept monotherapy does a better job than methotrexate alone and as good as the combination of the two drugs. 

Alone, etanercept was associated with a longer time to disease-worsening and a lower degree and proportion of patients whose condition deteriorated when compared to methotrexate monotherapy, the investigators said.

“Overall, the results of the SEAM-RA study provide information on the likelihood of success of discontinuing methotrexate and can inform general decision-making around RA treatment strategies. These results may be of particular interest to physicians and patients concerned about adverse events, such as nausea and fatigue, and long-term safety issues associated with methotrexate,” they added. [Eur J Med Chem 2018;158:502-516; N Engl J Med 2019;380:752-762]

The practical implications, according to the investigators, are to simplify care and minimize the medication burden in the setting of well-controlled RA.

SEAM-RA included 371 adult patients who received combination therapy with methotrexate plus etanercept, among whom 253 sustained remission (Simple Disease Activity Index [SDAI] score ≤3.3) through a 24‐week open‐label period. These patients then entered a 48‐week, double‐blind period and were randomized to continue receiving methotrexate only (n=101), etanercept only (n=101), or both (n=51).

Significantly more patients in the etanercept monotherapy group achieved the primary endpoint of SDAI‐defined remission at week 48 as compared with the methotrexate monotherapy group (49.5 percent vs 28.7 percent; p=0.004). [Arthritis Rheumatol 2021;73:759-768]

Furthermore, disease worsening occurred sooner for patients on maintenance methotrexate than for those who continued with etanercept or with the combination (p<0.001 for both comparisons).

Meanwhile, those who subsequently exhibited RA worsening in the double-blind treatment phase received rescue treatment with the combination regimen at the same doses used in the initial run‐in period.

SDAI‐defined remission was recaptured in 70–80 percent in each treatment group by 12 weeks after initiation of rescue therapy, with SDAI-defined low disease activity recaptured in even more patients. No new safety signals emerged.

Recapturing remission

“Disease flares in the setting of treatment withdrawal are a key concern. Though flares occurred with therapy withdrawal, these study results overall are reassuring, in that they demonstrate that when combination therapy was reinstituted following disease-worsening, remission was recaptured in [most] patients in both treatment-withdrawal groups,” the investigators pointed out.

Full recapture of remission after initiation of rescue therapy occurred at a median of 11 weeks in the methotrexate monotherapy group, 12 weeks in the etanercept monotherapy group, and 11.4 weeks in the combination therapy group.

“Time to recapture remission may be shorter when these strategies are implemented in real-world clinical practice, as very few patients received prednisone for disease flares in this trial,” the investigators noted. “These results provide a conservative estimate as to how methotrexate plus etanercept can induce recapture of remission without the use of steroids.”

Using the combination therapy group to serve as a comparator to the monotherapy groups, SEAM-RA showed the extent to which patients with sustained remission can experience RA worsening over an extended period because of the inherent variability in disease activity.

Consistent with the findings in a previous study, remission was not maintained in about one-half of the patients in the combination therapy group over the 48-week double-blind period. Many of them met the criteria for disease worsening, with a meaningful increase in disease activity (75–84 percent of patients having an SDAI score of >11) as opposed to multiple smaller fluctuations around an SDAI score of 3.3, the investigators said. [Arthritis Res Ther 2012;14:R68]

They also acknowledged that the study did not address gradual drug tapering. Nevertheless, “the treatment-withdrawal design in the setting of sustained stringent remission does provide a ‘best case’ scenario for patients in whom reduction of therapy is being considered.”

Simply reducing therapy, the investigators stressed, may not minimize the long-term safety concerns and slacken the need for monitoring.

*Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Rheumatoid Arthritis