Etanercept or Methotrexate Withdrawal in Rheumatoid Arthritis Patients in Sustained Remission

Abstract

Objective: Patients with rheumatoid arthritis (RA) in whom remission is achieved following combination therapy with methotrexate plus etanercept face an ongoing medication burden. This study was undertaken to investigate whether sustained remission achieved on combination therapy can be maintained with either methotrexate or etanercept monotherapy, as assessed following discontinuation of one or the other medication from the combination.

Methods: Of the 371 adult patients with RA who received combination therapy with methotrexate plus etanercept, remission (defined as a Simplified Disease Activity Index [SDAI] score of ≤3.3) was sustained in 253 patients through a 24-week open-label period. These 253 patients then entered a 48-week, double-blind period and were randomized to receive either 1) methotrexate monotherapy (n = 101), 2) etanercept monotherapy (n = 101), or 3) methotrexate plus etanercept combination therapy (n = 51). Patients who subsequently experienced disease-worsening received rescue therapy with the combination regimen at the same dosages as used in the initial run-in period. The primary end point was the proportion of patients in whom SDAI-defined remission was maintained without disease-worsening at week 48 in the etanercept monotherapy group as compared to the methotrexate monotherapy group. Secondary end points included time to disease-worsening, and the proportion of patients in whom SDAI-defined remission was recaptured after initiation of rescue therapy.

Results: Baseline demographic and clinical characteristics of the RA patients were similar across the treatment groups. At week 48, SDAI-defined remission was maintained in significantly more patients in the etanercept monotherapy group than in the methotrexate monotherapy group (49.5% versus 28.7%; P = 0.004). Moreover, as a secondary end point, sustained SDAI-defined remission was achieved in significantly more patients who received combination therapy than in those who received methotrexate monotherapy (52.9% versus 28.7%; P = 0.006). Time to disease-worsening was shorter in those who received methotrexate monotherapy than in those who received etanercept monotherapy or those who received combination therapy (each P < 0.001 versus methotrexate monotherapy). Among the patients who received rescue therapy, SDAI-defined remission was recaptured in 70-80% in each treatment group. No new safety signals were reported.

Conclusion: The efficacy of etanercept monotherapy was superior to that of methotrexate monotherapy and similar to that of combination therapy in maintaining remission in patients with RA. SDAI-defined remission was recaptured in most of the patients who were given rescue therapy. These data could inform decision-making when withdrawal of therapy is being considered to reduce treatment burden in patients with well-controlled RA.

Trial registration: ClinicalTrials.gov NCT02373813.

Figure 1

Flow chart of patient distribution in the study. At screening, patients with rheumatoid arthritis receiving methotrexate plus etanercept (combination therapy) were required to have a Simplified Disease Activity Index (SDAI) score of ≤3.3. After enrollment, patients continued receiving combination therapy and entered a 24‐week open‐label, run‐in period to identify patients in whom stable remission was achieved for randomization into the subsequent double‐blind, treatment‐withdrawal period. Patients with an SDAI score of >3.3 and ≤11 on 2 or more visits or an SDAI score of >11 at any time during the run‐in period were ineligible for the double‐blind period. Patients with SDAI‐defined remission at the end of the run‐in period and who met eligibility for the double‐blind period were randomized 2:2:1 into 1 of the 3 treatment groups.

Figure 2

Patients in whom remission (as defined by a Simplified Disease Activity Index [SDAI] score of ≤3.3) was achieved without disease‐worsening at week 48. The primary end point was comparison of the proportion of patients with SDAI‐defined remission at week 48 between the etanercept and methotrexate monotherapy groups, among patients in the primary analysis set. A secondary end point was comparison of the methotrexate monotherapy and combination therapy groups. Missing data were imputed using nonresponder imputation (patients with disease‐worsening were considered nonresponders). P values were estimated based on the chi‐square test with continuity correction.

Figure 3

Kaplan‐Meier curves of time to disease‐worsening in the 3 treatment groups (in the primary analysis set). The censor bars represent patients who did not have disease‐worsening at their last Simplified Disease Activity Index–defined remission assessment date. One patient discontinued treatment with methotrexate (MTX) on study day 0, and thus was no longer at risk and was censored. The median time to disease‐worsening in the etanercept (ETN) monotherapy (Mono) group and the combination (Combo) therapy group was not estimable (NE) because the cumulative event rate in these 2 groups at the end of the study period at 336 days (48 weeks) was 59.6% and 65.2%, respectively (i.e., did not reach or fall below 50%). *P values are nominal and compare the etanercept‐containing groups with the methotrexate monotherapy group using a 2‐sided log‐rank test. 95% CI = 95% confidence interval.

Figure 4

Cumulative proportion of patients in whom Simplified Disease Activity Index (SDAI)–defined remission (A) and low disease activity (B) were recaptured after initiation of rescue therapy (the rescue analysis set). The rescue analysis set consisted of 52 patients in the methotrexate (MTX) monotherapy (Mono) group, 36 patients in the etanercept (ETN) monotherapy group, and 15 patients in the combination (Combo) therapy group. On the X‐axis, the value of 0 represents the time point of initiation of rescue therapy. Once SDAI‐defined remission or low disease activity was recaptured, patient numbers remained as is for the subsequent weeks (even if remission or low disease activity status was lost at a later time).