PRESERVE Study: HAQ, BMI and Age Predict Responses to Combo Therapy Save

Rheumatoid arthritis (RA) patients who were younger and who had lower body mass index (BMI), Health Assessment Questionnaire (HAQ) scores, and less disease activity at baseline were most likely to achieve remission after combination etanercept (Enbrel) and methotrexate induction therapy, a post hoc analysis of the PRESERVE trial found.

Patients who failed to achieve sustained remission with induction therapy and ones with worse disease activity and patient-reported outcomes soon after starting maintenance therapy were most likely to lose remission, reported Josef S. Smolen, MD, of the Medical University of Vienna, and colleagues.

"This result underscores and reinforces the current treat-to-target approach and the importance of adjusting treatment in patients who are not achieving the lowest levels of disease activity currently recommended in the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) treatment guidelines, as it suggests that the depth and duration of response are relevant," they wrote online in Arthritis Research & Therapy.

In 2013, the PRESERVE trial showed that after etanercept was withdrawn, etanercept-methotrexate combinations were more effective in maintaining low RA disease activity than methotrexate alone. In this post hoc analysis, the researchers aimed to identify potential predictive markers that induced remission or caused it to fail over time.

When PRESERVE was designed, the new, more stringent ACR and EULAR remission criteria had not been published. While Disease Activity Score in 28 joints (DAS28) <2.6 no longer defines remission, the authors used it in this analysis to be consistent with the primary manuscript, also looking at Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) remission values.

The PRESERVE trial studied adults with active RA who had moderate disease activity (DAS28>3.2 and ≤5.1 at baseline). All patients enrolled in the initial open-label period were treated for 36 weeks with etanercept 50 mg once weekly plus methotrexate.

At the start of the open-label period, 83% of patients were women, average age was 48, and mean DAS28, SDAI, and CDAI scores were 4.4, 19.1, and 17.8.

After 36 weeks, patients who achieved sustained low disease activity (an average DAS28≤3.2 from weeks 12 to 36 and DAS28≤3.2 at week 36) were randomized to continue weekly subcutaneous injections of etanercept 50 mg, reduce the etanercept dose to 25 mg, or withdraw etanercept and receive placebo injections, all with background methotrexate, for a 52-week double-blind period.

While similar proportions of patients treated with etanercept 50 mg and etanercept 25 mg maintained remission in the double-blind period, withdrawing etanercept resulted in a loss of remission in many patients.

Several continuous baseline factors appeared to predict DAS28, SDAI, and CDAI remission after 36 weeks. Lower baseline DAS28, SDAI, and CDAI, younger age, BMI under 30,and lower HAQ score were significant predictors of all three endpoints.

For all three treatments, the strongest predictors of loss of DAS28 remission included failure to achieve sustained remission with induction therapy (DAS28<2.6 at weeks 12, 20, 28, and 36), higher DAS28, SDAI, and CDAI at randomization and at 1 month, increase in DAS28, SDAI, and CDAI at 1 month, and increase in DAS28, CDAI, SDAI components and patient-reported outcomes at 1 month. SDAI and CDAI remission had similar predictors.

"The lower the DAS28, and thus the lower the residual disease activity level, the greater the likelihood of sustained response," the researchers wrote, noting that predictors for sustained SDAI and CDAI remission "further support the conclusion of a better outcome with lower disease activity and maintenance of a good response at the time of withdrawal."

"These findings may help guide clinicians' decision-making as they treat patients to remission and beyond," they added.

The PRESERVE trial and its analyses have several limitations. The study excluded patients with mild or severe disease activity or with certain comorbid diseases. Predictors of remission analyses were limited to data collected in the first 36-week period of the PRESERVE trial.

Because SDAI and CDAI remission were more stringent endpoints, with fewer patients achieving them than DAS28 remission, analyses about SDAI and CDAI remission loss had less power to detect differences than analyses about the loss of DAS28 remission.

This post-hoc analyis of the PRESERVE trial was sponsored by Pfizer.