Maxime Verhoeven

70 Chapter 4 validated model was applied in the combined derivation and validation cohort. This model, without ABCB1 rs1045642 genotype and ABCC3 rs4793665 genotype, had an AUC of 0.75, meaning that it classified 75% of the insufficient responders correctly. Currently, according to the EULAR treatment guidelines MTX is the first-line therapy in RA. Treatment is only up-scaled after 3 to 6 months of insufficient response to MTX, despite evidence supporting a ‘window of opportunity’ for targeted treatment. 1,17 This window of opportunity is a limited period between diagnosis and RA progression in which the disease could still be modified, radiographic damage/functional disability could be limited and progression could be slowed down upon early control of disease activity, for which sufficient treatment is required. 17 Our prediction model could assist in identification of insufficient responders at diagnosis: for those with high probability of insufficient response to MTX, additional biologics or JAK-inhibitors could be prescribed, while for patients with low probabilities of insufficient response these expensive treatments could be spared. This distinction at diagnosis could save precious time for insufficient responders, allowing earlier control of disease activity resulting in better long-term outcomes. We externally validated the model for the first time in its entirety as, besides the clinical and laboratory predictors, the lifestyle predictors (BMI and smoking) were also examined in the U-Act-Early cohort (as opposed to the initial validation in the MTX- Rotterdam cohort which lacked the life-style predictors). 9 The strongest predictor was high disease activity at baseline (DAS28 >5.1) confirming previous findings. 7,18 Due to differences in treatment intensities (i.e., MTX dose and co-medication) between the derivation and the validation cohort, we investigated whether the model was applicable at 6 months despite step-up treatments after the 3-month mark. Indeed 71% of the non-responders to MTX were classified correctly, which was similar to the 75% in the tREACH derivation cohort at 6 months. In the combined cohort, all predictors except for ABCB1 and ABCC3 genotypes significantly contributed to the predictive power of the model. Addition of ABCB1 and ABCC3 genotypes to the model showed only minimal improvement, resulting in an absolute change in AUC of 0.01, which was not statistically significant. A meta-analysis on the relationship between ABCB1 genotype and response to MTX in 2014 RA patients showed an association between this genotype and response to MTX, yet our patient group was too small to validate this result. 9 Another recent GWAS study did not show a relationship between ABCB1 or ABCC3 and treatment response. 19 Since the differences in predictive power were minor and the effect of ABCC3 genotype pointed in opposite directions in the two cohorts, possibly indicating a spurious finding, we excluded both genotypes from the model. In agreement with our study, increased BMI (obese >30 kg/m 2 ) was previously found to be associated with insufficient response to MTX in RA patients. 20,21 It is postulated that the effect of BMI on non-response to MTX could be due to the release