Earlier is better when treating rheumatoid arthritis: but can we detect a window of opportunity?

Abstract

Objectives: The window of opportunity (WOO) hypothesis suggests a limited time frame to stop rheumatoid arthritis (RA). We hypothesised that a WOO could either be represented by a hyperbolic ('curved') decline in the chance to achieve the outcome sustained drug-free remission (sDFR) over time, after which achieving sDFR is not possible anymore, or by a more gradual linear decline approaching zero chance to achieve sDFR.

Methods: Patients with RA (symptom duration <2 years) were included from two randomised trials: BehandelStrategieën (BeSt), n=508 and Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED), n=479. Cox-regression was performed to assess the shape of the association between symptom duration and sDFR (Disease Activity Score<1.6, no disease-modifying anti-rheumatic drugs for ≥1 year) for patients starting slow-acting monotherapy (IMPROVED, BeSt) or fast-acting combination therapy (BeSt). Likelihood ratio tests were used to compare the fit of linear and non-linear models in both databases separately. Predictions from the best fitting models were used to assess whether the absolute risk to achieve sDFR approaches zero with increasing symptom duration.

Results: In BeSt and IMPROVED, 54/226 and 110/421 patients achieved sDFR with fast-acting treatment, and 53/243 (BeSt) with slow-acting treatment. Non-linear models did not fit better than linear models (fast-acting treatment BeSt p=0.743, IMPROVED p=0.337; slow-acting treatment BeSt p=0.609). After slow-acting monotherapy, linear models declined steeper. None of the models approached zero chance to achieve sDFR over time.

Conclusions: The chance to achieve sDFR decreased gradually over time, and decreased fastest in patients starting slow-acting monotherapy. In both treatment groups, we found no evidence for a WOO within 2 years symptom duration.

Keywords: Bone mineral density; Corticosteroids; DMARDs (biologic); DMARDs (synthetic); Disease activity; Osteoarthritis; Osteoporosis; Rheumatoid arthritis.

Figure 1

Representation of time-to-outcome curves for the relationship between time to treatment initiation and the chance to achieve sDFR. (A) Shows a non-linear relationship between time of treatment onset and the outcome sDFR. There is a short time frame with a high chance of achieving the outcome (until the bend in the curve) and a lost opportunity thereafter. This would indicate a WOO. (B) Shows a linear relationship between time of treatment onset and the outcome sDFR, which is indicative of a more gradual decline in the chance of achieving the outcome. If this chance approaches zero with increasing symptom duration, this would also be indicative of a WOO. sDFR, sustained drug-free remission; WOO, window of opportunity.

Figure 2

The WOO and slow- versus fast-acting DMARDs. In this figure, the potential effect of slow- versus fast-acting DMARDs on the WOO is drawn for a non-linear scenario. The same hypothesis could be applied in a linear scenario. DMARDs, disease-modifying anti-rheumatic drugs; WOO, window of opportunity.

Figure 3

Best fit models to depict the relationship between symptom duration and sDFR. Panels show data from the BeSt (A) and IMPROVED (B) trial. Applying natural cubic spline functions (allowing a curved relationship) did not result in a superior fit compared to a linear model. sDFR, sustained drug-free remission.

Figure 4

Absolute risk to achieve sDFR with increasing symptom duration in BeSt (A) and IMPROVED (B). Predictions were calculated based on the best fitting models, as shown in figure 3. sDFR, sustained drug-free remission.