High remission and low relapse with prolonged intensive DMARD therapy in rheumatoid arthritis (PRINT): A multicenter randomized clinical trial

Abstract

Objectives: To determine whether prolonged intensive disease-modifying antirheumatic drug (DMARD) treatment (PRINT) leads to high remission and low relapse rates in patients with severe rheumatoid arthritis (RA).

Methods: In this multicenter, randomized and parallel treatment trial, 346 patients with active RA (disease activity score (28 joints) [DAS28] (erythrocyte sedimentation rate [ESR]) > 5.1) were enrolled from 9 centers. In phase 1, patients received intensive treatment with methotrexate, leflunomide, and hydroxychloroquine, up to 36 weeks, until remission (DAS28 ≤ 2.6) or a low disease activity (2.6 < DAS28 ≤ 3.2) was achieved. In phase 2, patients achieving remission or low disease activity were followed up with randomization to 1 of 2 step-down protocols: leflunomide plus hydroxychloroquine combination or leflunomide monotherapy. The primary endpoints were good European League Against Rheumatism (EULAR) response (DAS28 (ESR) < 3.2 and a decrease of DAS28 by at least 1.2) during the intensive treatment and the disease state retention rate during step-down maintenance treatment. Predictors of a good EULAR response in the intensive treatment period and disease flare in the maintenance period were sought.

Results: A good EULAR response was achieved in 18.7%, 36.9%, and 54.1% of patients at 12, 24, and 36 weeks, respectively. By 36 weeks, 75.4% of patients achieved good and moderate EULAR responses. Compared with those achieving low disease activity and a high health assessment questionnaire (HAQ > 0.5), patients achieving remission (DAS28 ≤ 2.6) and low HAQ (≤ 0.5) had a significantly higher retention rate when tapering the DMARDs treatment (P = 0.046 and P = 0.01, respectively). There was no advantage on tapering to combination rather than monotherapy.

Conclusions: Remission was achieved in a proportion of patients with RA receiving prolonged intensive DMARD therapy. Low disease activity at the start of disease taper leads to less subsequent flares. Leflunomide is a good maintenance treatment as single treatment.

Figure 1

Trial profile. HCQ = hydroxychloroquine, LDA = low disease activity, LEF = leflunomide, MTX = methotrexate.

Figure 2

EULAR response for the modified intention-to-treat population of rheumatoid arthritis patients with intensive disease-modifying antirheumatic drug treatment. The prevalence of patients achieving good EULAR response increased 17% to 18% every 12 weeks. EULAR = European League Against Rheumatism.

Figure 3

Kaplan–Meier curves for disease activity retention over the course of 48-week maintenance treatment. (A) Retention rate in patients with different disease activity. There were significantly higher disease retention rate in patients achieving remission (DAS28 ≤ 2.6) than those achieving LDA (2.6 < DAS28 ≤ 3.2) (P = 0.046). (B) Retention rate in patients with different functional activity. There were significantly higher disease retention rate in patients having low HAQ (≤0.5) than those having HAQ > 0.5 (P = 0.01). (C) Retention rate in patients with different DAS28 and HAQ. It had been shown that patients achieving both remission and low HAQ had the highest disease retention rate during the maintenance period (DAS28 ≤ 2.6/HAQ ≤ 0.5 vs 2.6 < DAS28 ≤ 3.2/HAQ > 0.5, P = 0.02; vs DAS28 ≤ 2.6/HAQ > 0.5, P = 0.04; vs 2.6 < DAS28 ≤ 3.2/HAQ ≤ 0.5, P = 0.25, respectively). DAS28 = disease activity score (28 joints), HAQ = health assessment questionnaire, LDA = low disease activity.