Methotrexate (MTX) is the cornerstone treatment in juvenile idiopathic arthritis (JIA). Nevertheless, MTX is insufficiently efficacious and leads to adverse effects in some JIA patients, which compromises attainment of complete disease control. In such cases, combination therapies with biologicals are given, even at MTX start, before knowing the patients’ MTX response. However, clinicians should know, before or early after MTX start, which patients will benefit from MTX only and which patients will not, thus requiring addition of biologicals. To make such tailor-made treatment decisions, clinicians necessitate tools to optimise MTX treatment. In part I, we investigate tools to steer tailor-made therapeutic decisions in JIA. In chapter 4, we developed and validated a clinical-genetic prediction model for MTX non-response, which classified 72% of patients correctly and 65% upon external validation. Using the model, patients who are likely not to respond to MTX will receive biologicals early, whereas those responsive to MTX will be spared costly biologicals with potentially serious adverse effects. In chapter 5, we determined that long-chain MTX polyglutamates (MTX-PG), at 3 months after MTX start, were associated with lower 3-month and one-year disease activity. MTX-PGs could guide clinicians to escalate MTX dose in patients with low polyglutamation rate or to give biologicals to patients with adequate polyglutamation, but insufficient MTX response. In part II, we focus on MTX intolerance – gastrointestinal and behavioural symptoms occurring after, before and when thinking of MTX. In chapters 7 and 8, we determined, using the Methotrexate Intolerance Severity Score (MISS), that MTX intolerance prevalence reached 50.5% (n=297) in JIA and 11% in adult arthritis patients (n=291), higher for parenteral than for oral MTX. We conclude that arthritis patients should be monitored with MISS, as it allows early MTX intolerance detection and offers opportunity for timely MTX intolerance treatment. In chapter 9, we compared the therapeutic effect of oral MTX and behavioural therapy or parenteral MTX with oral MTX combined with an antiemetic on MTX intolerance. Behavioural therapy was not superior in targeting MTX intolerance; instead, all strategies were beneficial in the first enrolment week, suggesting the crucial role of trial participation. We conclude that treatment strategies for MTX intolerance should be tailored, based on patients’ motivations and expectations. In chapter 10, we developed and validated a clinical prediction model for MTX intolerance, which classified 77.5% of patients correctly, and 66.7% after internal validation. With this prediction model, patients at risk of developing MTX intolerance could be identified and treated timely. In part III, chapter 11, we focus on MTX effects on regulatory (Treg) and effector (Teff) T cells at MTX start and 3/6 months upon start. Although Treg were not affected by MTX, Teff proliferation and plasma IFNγ at 6 months were enhanced, indicating that MTX does not attenuate but enhances effector cell function. This is contrary to the common belief that low-dose MTX in rheumatic diseases has immunosuppressive properties. This thesis demonstrates that tailor-made MTX treatment is possible and should be applied in order to offer optimal treatment to all JIA patients. Future studies should focus on validation and refinement of described tools in large cohorts, followed by their application in daily clinical practice.