Maxime Verhoeven

32 Chapter 2 No overall pooled effect estimate was given as studies were highly heterogeneous in study design regarding e.g., specific drug regimen and remission outcome used. We therefore defined groups of more homogeneous studies based on specific remission outcomes and characteristics of drug regimen. Results within these groups show that heterogeneity is typically low, and therefore we pooled the effect estimates. However, in some of these groups, heterogeneity was moderate, based on differences in study design, medical treatment, risk of bias and/or patient characteristics (I 2 >50%, see Figure 1 and 2). One surprising finding was that the added value of a remission-induction strategy was found to be limited and non-statistically significant when compared to a single csDMARD-initiating strategy with GC bridging therapy. This may suggest that the current early start of therapy, including a treat-to-target approach with swift step-up treatment adjustments, achieves already very good results when the initial delay in treatment effectives covered by the bridging therapy. Contrary to expectation, similar beneficial outcomes for patients treated within the window of opportunity were found when compared with those for patients treated outside the window of opportunity. However, only a limited number of studies reported data on symptom duration which is notoriously difficult to define, and our study was not specifically designed to test the window of opportunity hypothesis. Outside of our study, in some papers a difference in effectiveness of treatment has been shown in favor of patients treated within the window of opportunity. 2,39 In general, long-term effectiveness outcomes were not different between a remission-induction strategy and a single csDMARD-initiating strategy probably due to the widely applied the treat-to-target principle. 1 Results of our systematic literature review are in line with an earlier performed systematic literature review, which included only remission-induction strategies using a b/tsDMARD in the experimental arm. 40 We, uniquely include also combination csDMARD based remission-induction strategy arms, providing results applicable also for countries with limited availability of bDMARDs. Besides, we evaluated several established remission definitions according to validated disease activity indices and the Boolean definition. 1 No data on radiographic progression was reported, because of the limited study duration of most included studies; even over 2 years, radiographic progression is absent or modest at most in treat-to-target studies in early RA. 41,42 Only some of the long- term extension studies reported on radiographic progression, but did not show any statistically significant differences. The majority of all included studies, i.e., 20/29 (69%), were RCTs with no to moderate risk of bias. The longer term follow-up studies were follow ups of RCTs, in which the effectiveness was maintained, indicating the quality of keeping to the treat-to-target principle.