Effectiveness of four dynamic treatment strategies in patients with anticitrullinated protein antibody-negative rheumatoid arthritis: a randomised trial

Abstract

Objective: To determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis.

Methods: In the BeSt study, 184 ACPA-negative patients were randomised to: (1) sequential monotherapy, (2) step-up therapy, (3) initial combination including prednisone, (4) initial combination including infliximab. Treatment was targeted at the disease activity score (DAS) ≤2.4. Early response and 10-year outcomes were compared between the four strategy-arms in ACPA-negative patients.

Results: ACPA-negative patients achieved more short-term functional improvement from initial combination therapy than when on monotherapy (at month 3, mean Health Assessment Questionnaire (HAQ) 0.71 vs 0.98, p=0.006; at month 6, 0.59 vs 0.87, p=0.004). Functional ability over time was comparable between the strategy-arms (p=0.551) with a mean HAQ of 0.6 at year 10 (p=0.580 for comparison across the strategy-arms). 10-year radiographic progression was negligible (median 0.5) and comparable between the 4 strategy-arms (p=0.082). At year 10, remission was achieved by 11/40 (28%), 9/45 (20%), 17/56 (30%) and 17/43 patients (40%) in strategy-arms 1-4, respectively (p=0.434). Over time, similar remission percentages were achieved in all strategy-arms (p=0.815). 18%, 16%, 20% and 21% in strategy-arms 1 to 4 (p=0.742) were in drug-free remission at year 10, with a median duration of 60 months across the arms.

Conclusions: Initial combination therapy with methotrexate, sulfasalazine and prednisone, or methotrexate and infliximab, is the most effective treatment strategy for ACPA-negative patients, resulting in earlier functional improvement than when on initial methotrexate monotherapy. After 10 years of targeted treatment, in all strategy-arms favourable clinical outcomes were achieved and radiographic progression was limited.

Trial registration number: NTR262, NTR265.

Keywords: Ant-CCP; Rheumatoid Arthritis; Treatment.

Figure 1

(A) Functional ability, (B) DAS-remission percentages and (C) probability plot of radiographic joint damage progression from baseline to year 10 (completer analysis). (B) DAS-remission was defined as disease activity score (DAS) <1.6. Percentages reflect the number of patients in DAS-remission as part of the completers. More patients missed the visits before the yearly visits at year 5 and 10, because they were running behind on their schedule. Low attendance makes the DAS-remission percentages at these visits difficult to interpret. Mean disease activity did not show this decrease (data not shown). (C) Patients in strategy arms 1 and 4 had numerically less progression compared to strategy arms 2 and 3, statistically not significant (p=0.639). In strategy arms 1 and 4, patients with progression (defined as ≥0.5 SHS) had moderate disease activity during early visits (mean DAS±SD 2.99±1.14 at 3 months and 2.45±1.13 at 6 months) and 46% were rheumatoid factor (RF) positive. In strategy arms 2 and 3, patients with progression (defined as ≥0.5 SHS) had also moderate disease activity at early visits (mean DAS±SD 2.99±1.16 at 3 months and 2.46±1.14 at 6 months) and 42% were RF-positive. HAQ, health assessment questionnaire (range 0–3); SHS, Sharp van der Heijde score.

Figure 2

Kaplan-Meier Curves showing drug survival in strategy arms 1 and 2. (A) Initial methotrexate monotherapy, n=84; (B) Switching to sulfasalazine monotherapy in strategy arm 1, adding sulfasalazine to methotrexate in strategy arm 2, n=46; (C) Switching to leflunomide monotherapy in strategy arm 1, adding hydroxychloroquine to methotrexate and sulpsalazine in strategy arm 2, n=35. Discontinuation of drugs is due to insufficient response, toxicity or other reasons. The lines indicate the percentage of patients in strategy arms 1 and 2 who are treated according to the concerned treatment step.