Predictors of remission with etanercept-methotrexate induction therapy and loss of remission with etanercept maintenance, reduction, or withdrawal in moderately active rheumatoid arthritis: results of the PRESERVE trial

Abstract

Background: The aim was to analyze characteristics that predict remission induction and subsequent loss of remission in patients with moderately active rheumatoid arthritis (RA) who received full-dose combination etanercept plus methotrexate induction therapy followed by reduced-dose etanercept or etanercept withdrawal.

Methods: Patients with Disease Activity Score based on 28-joint count (DAS28) >3.2 and ≤5.1 received open-label etanercept 50 mg once weekly (QW) plus methotrexate for 36 weeks. Those who achieved DAS28 low disease activity by 36 weeks were randomized to double-blind treatment with etanercept 50 mg or 25 mg QW plus methotrexate or placebo plus methotrexate for 52 weeks. All analyses were adjusted for the continuous baseline variables of their respective remission outcomes.

Results: Younger age, body mass index (BMI) <30 kg/m², and lower Health Assessment Questionnaire (HAQ) score at baseline were significant predictors of week-36 remission (P < 0.05) based on DAS28, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). Baseline DAS28, SDAI, and CDAI were significantly predictive of all three remission endpoints (P < 0.05). For all three treatments, the strongest predictors of loss of DAS28 remission included failure to achieve sustained remission (DAS28 < 2.6 at weeks 12, 20, 28, and 36) with induction therapy, higher DAS28/SDAI/CDAI at randomization and at 1 month, increase in DAS28/SDAI/CDAI at 1 month, and increase in DAS28/CDAI/SDAI components and patient-reported outcomes (PROs) at 1 month. With the exception of not achieving sustained remission, very similar significant predictors were observed for loss of SDAI and CDAI remission.

Conclusion: These findings suggest that patients with moderately active RA who are younger and have lower BMI, lower HAQ, and lower disease activity at baseline are most likely to achieve remission when receiving combination etanercept and methotrexate induction therapy. In addition, patients who fail to achieve sustained remission with induction therapy and those with worse disease activity and PROs at early time points after initiating maintenance therapy with a full-dose or reduced-dose etanercept-methotrexate regimen or methotrexate monotherapy are most likely to lose remission across all treatment arms. These findings may help guide clinicians' decision-making as they treat patients to remission and beyond.

Trial registration: ClinicalTrials.gov, NCT00565409 . Registered on 28 November 2007.

Keywords: Etanercept; Low disease activity; Methotrexate; Remission; Rheumatoid arthritis; Treatment.

Fig. 1

Continuous and categorical baseline predictors of disease activity score based on 28 joints (DAS28) (a), Simplified Disease Activity Index (SDAI) (b), and Clinical Disease Activity Index (CDAI) (c) remission using univariate logistic regression (unadjusted). If the 95% CI does not contain the value 1.0, the predictor is statistically significant at α = 0.5. Non-significant predictors, black; significant predictors, gray. For continuous predictors with odds ratios >1, higher values are associated with a greater likelihood of remission. For numeric categorical predictors with odds ratios >1, higher numeric subgroups are associated a greater likelihood of remission (e.g., patients with body mass index (BMI) 18.5–25 kg/m² are more likely to achieve DAS28 remission than patients with BMI <18.5 kg/m²); for nominal categorical predictors, the first named subgroup is associated with a greater likelihood of remission (e.g., anti-citrullinated peptide antibody (ACPA) + patients are more likely to achieve DAS28 remission than ACPA- patients). Conversely, for continuous predictors with odds ratios <1, lower values are associated with a greater likelihood of remission. For numeric categorical predictors with odds ratios <1, lower numeric subgroups are associated with a greater likelihood of remission (e.g., patients who are ≤40 years of age are more likely to achieve DAS28 remission than patients who are >40 years of age); for nominal categorical predictors with odds ratios <1, the second named subgroup is associated with a greater likelihood of remission (e.g., patients with erythrocyte sedimentation rate (ESR) levels ≤ upper limit of normal (ULN) are more likely to achieve DAS28 remission than patients with ESR > ULN). BL, baseline; CI, confidence interval; CRP, C-reactive protein; HAQ, Health Assessment Questionnaire; JSN, joint space narrowing: mTSS, modified total Sharp score: PGA, physician global assessment; PtGA patient global assessment; RF, rheumatoid factor. Analyses were adjusted for baseline DAS28, SDAI, and CDAI (respectively). Patients included in the DAS28, SDAI, and CDAI remission models: n = 763, n = 755, and n = 762, respectively. Radiographic variables were excluded from the stepwise analyses because 55 patients did not have radiographic data

Fig. 2

Select continuous and categorical baseline predictors of Disease Activity Score based on a 28-joint count (DAS28) (a), Simplified Disease Activity Index (SDAI) (b), and Clinical Disease Activity Index (CDAI) (c) remission using stepwise models (adjusted for other variables). If the 95% confidence interval (CI) does not contain the value 1.0, the predictor is statistically significant at α = 0.5. Non-significant predictors, black; significant predictors, gray. HAQ, health assessment questionnaire

Fig. 3

Proportions of patients who were not in Disease Activity Score based on a 28-joint count (DAS28) remission in the double-blind period. ETN, etanercept; MTX, methotrexate

Fig. 4

Strongest sets of predictors of loss of Disease Activity Score based on a 28-joint count (DAS28) remission (a), DAS28 remission plus change in DAS28 ≥ 0.6 (b), Simplified Disease Activity Index (SDAI) remission (c), and Clinical Disease Activity Index (CDAI) remission (d) in the double-blind period by treatment group using stepwise models. CI, confidence interval; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HAQ, health assessment questionnaire; PGA, physician global assessment; PtGA, patient global assessment; RF, rheumatoid factor; SJC, swollen joint count; ULN, upper limit of normal; VAS, visual analog scale

Fig. 5

Predicted probability (95% CI) of the loss of Disease Activity Score based on a 28-joint count (DAS28) remission and low disease activity (LDA) in patients receiving reduced-dose combination therapy or methotrexate monotherapy in the double-blind period based on mean DAS28 at week 36 of the open-label period, using logistic regression models. Circles at the top, patients who lost response; circles at the bottom, patients who did not lose response; smooth line, model-predicted probability of loss of response as a function of week-36 DAS28; shadowed area, 95% CI

Fig. 6

Proportions of patients who lost Disease Activity Score based on a 28-joint count (DAS28) remission (a), DAS28 remission and had a change in DAS28 ≥ 0.6 (b), Simplified Disease Activity Index (SDAI) remission (c), and Clinical Disease Activity Index (CDAI) remission (d) at least once at any time point in the double-blind period by duration of remission in the open-label period. n/N, numbers of patients who lost remission in the double-blind period/numbers of patients who had remission at specified time points in the open-label period. Patients included in the loss of remission models (i.e., patients with remission at week 36). ETN, etanercept; MTX, methotrexate