Maxime Verhoeven

72 Chapter 4 the clinical goal. Taking into consideration the “window of opportunity” 17 for optimal treatment, we consider it crucial to adequately treat insufficient MTX responders with additional bDMARDs/tsDMARDs. Therefore, our goal for this prediction model was to identify as many insufficient responders as possible, while at the same time attempting to restrict the use of bDMARDs/tsDMARDs to those patients who really need them, hence to avoid misclassification of sufficient responders. Considering this, a cut-off probability of 70% (of insufficient response) could be chosen. At this cut-off, 75% of patients classified as insufficient responder match actual insufficient responders (PPV) and could be treated with additional bDMARDs/tsDMARDs. Additionally, at this cut-off 86% of all sufficient responders would be correctly classified as such (specificity) and could be spared additional treatment. The importance of erythrocyte-folate for the predictive power of the model implies that this model is specific in predicting insufficient response to MTX, as MTX is structurally similar to folate. Hence, low erythrocyte folate levels are possibly a surrogate measure for poor MTX absorption, transportation and MTX accumulation in the cell, as described previously. 14 However, it is possible that a certain proportion of insufficient responders to MTX are difficult-to-treat RA patients who are poorly responsive to various b/ts DMARDs. 26,27 So far, we cannot identify difficult-to-treat RA patients in advance. Furthermore, as recently argued, treatment strategies could be more important than specific drugs, implying that these patients could still benefit from quicker and more aggressive treatment to reach a certain treatment target when earlier identified as insufficient responders. 28,29 Conclusion We successfully externally validated our previously published prognostic prediction model of insufficient response to MTX, which correctly classified 75% of insufficient responders at 3 months and 71% of non-responders at 6 months of treatment. The model can be used in clinical practice to identify insufficient responders to MTX with the goal of treating them with an additional biologic or JAK-inhibitor as early as possible to reduce disease activity and limit joint damage. Application of the tool by means of a clinical trial is warranted.