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Summary Introduction Rheumatoid Arthritis (RA) is an autoimmune-induced inflammatory disease with a worldwide prevalence of about 5 per 1000 adults. This chronic systemic disease is characterized by inflammation of mainly the small joints of hands and feet with pain, swelling and stiffness. If insufficiently treated, this inflammatory process can lead to worse physical functioning, impaired work and social participation and eventually joint damage through loss of articular cartilage and bone erosions. It is crucial to start an effective treatment in patients with RA as soon as possible to reach the target of remission or at least low disease activity. Treatment should be rapidly adapted in case the target is not yet met, according to the 'treat to target' principle. Objectives This PhD research project is based on data of the 2-year Care in early RA (CareRA) trial and the 3-year observational CareRA plus follow-up study. The overall objective of this thesis was to evaluate the long-term effectiveness of intensive treatment strategies used in CareRA, in order to define an optimal approach for treating patients with early RA. In this perspective, the efficacy, safety, sustainability of treatment response and need for treatment adaptations, associated with these regimes, were assessed up until 2 and 5 years after treatment initiation. Additionally, the applicability of these regimens in clinical practice was investigated, by addressing the following questions: whether presence of significant comorbidities would affect outcomes, which maintenance therapy should be used once patients reach a sufficient clinical response and to what extent do rheumatologists adhere to these strategies in a setting close to daily clinical practice. Results The first chapter explored the effectiveness of initial treatment strategies for patients with early RA on the long term. We concluded that an initial combination of methotrexate (MTX) and a glucocorticoids (GCs) bridging scheme (COBRA Slim) including a subsequent treat-to-target approach, can lead to a good and sustained disease control on the long term, irrespective of patient's prognosis. This COBRA Slim regimen resulted in comparable outcomes after 2 and 5 years as more complex regimens, and showed a more favourable safety profile. Therefore, this strategy with fewer drugs may avoid unnecessary overtreatment in patients sufficiently responding. Furthermore, the COBRA-Slim strategy with its consecutive adaptation steps seemed to result in biologicals being initiated at a later stage, assuming a better cost-effectiveness, which was confirmed in a separate cost-effectiveness analysis by our research group. Therefore, the COBRA Slim scheme was considered as an efficacious, safe and cost-effective treatment strategy for every patient with RA. In the first part of the second chapter we explored how we could further refine the optimal treatment strategy for early RA, by investigating the effectiveness of different maintenance therapies once patients achieved a well-controlled disease state. Firstly, we compared the effectiveness of stepping down treatment to either MTX or to leflunomide (LEF) in a randomized setting, in patients who achieved low disease activity after an initial combination of MTX, LEF and a GCs bridging scheme. Our results indicated that within this setting, it was more beneficial to step down to MTX than to LEF, since this maintenance therapy led to numerically better clinical outcomes after 65 weeks, had a better retention rate with 20% more patients remaining on MTX monotherapy and was tolerated equally well. These findings could also hold true for patients achieving low disease activity after addition of LEF to MTX monotherapy because of an initial insufficient response, although we were unable to formally demonstrate this based on this trial design. In the second part of the second chapter, we evaluated to what extent rheumatologists adhered to the treat-to-target (T2T) approach within the treatment strategies studied. We defined adherence as performing a dose escalation or changing/adding DMARDs in case low disease activity was not achieved. Results indicated that applying T2T strictly during the first 2 years of treatment was challenging, since in only half of visits theoretically requiring a DMARD adaptation, treatment was intensified. The most frequent reason not to intensify treatment, given by rheumatologists during the first study year, was that they considered the disease already well-controlled. Strict application of T2T guidance at every visit was associated with higher remission rates after 2 years, after adjusting for factors known to potentially influence chances at remission. However, an exact cause-effect relationship could not be demonstrated, due to the potential effect of various other factors. Furthermore, stating that T2T should always be applied without restriction, could also lead to a risk for overtreatment in certain cases and hence increased occurrence of (dose related) DMARD side effects. Therefore, we advocate for a flexible tight control, which states that decisions to adapt treatment should not be made blindly based on ambiguous or too ambitious target measures but should be based on the individual clinical picture. In the third chapter, we evaluated the prevalence of comorbidities in early RA patients before initiation of DMARD treatment and the impact of comorbidities on treatment response. We demonstrated that even in this early phase of the disease there was a high prevalence of comorbidities with nearly half of patients in our sample having at least one clinically relevant comorbidity. Additionally, we showed that having a comorbidity, but also the degree of comorbidity before treatment initiation was significantly related to worse functionality, worse disease control and worse physical health related quality of life as well as more hospitalizations. This effect of comorbidity on treatment response, could apparently not be mitigated by using intensive treatment regimens and applying the treat-to-target principle. Because of this impact of comorbidity on clinically important outcomes, the focus of caring for patients with newly diagnosed RA should not only be on controlling disease activity as soon as possible, which is necessary for all patients, but also on the management of comorbidities. Since many comorbidities are amenable to preventive and therapeutic measures, they should be detected and taken care of at an early stage, in order to reduce their impact on the outcomes in RA. Conclusion This doctoral thesis gives indications on how care for patients with early RA can be improved. Firstly, an initial combination of MTX and a GC bridging scheme led to sustained effectiveness and was well tolerated in patients with early RA. Secondly, stepping down treatment to MTX instead of to LEF was more beneficial in patients who achieved a good disease control after an initial intensive combination of both these drugs. Thirdly, it seems that we should be strict in our evaluation of the disease status but flexible in our approach to improve it further. And lastly, comorbidities should be screened for and managed already from disease onset since they affect clinical outcomes despite intensive treatment. These results provide directions to optimize pharmacological treatment and management of early RA, with the overall aim to improve patients' health related quality of life.

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Abstract Background. Intensive remission induction therapy consisting of methotrexate (MTX) and short-term glucocorticoids (GC) is currently recommended for patients with early rheumatoid arthritis (RA). If it would be possible to predict which patients would respond insufficiently to this treatment, they could be fast-tracked to other treatment strategies, in order to make maximum use of the early window of opportunity. Objective. To summarize potential determinants of therapy response to currently recommended non-biological intensive remission induction therapy in patients with early RA. Methods. We performed a systematic literature review of studies that identified predictors of remission in RA patients, treated with at least MTX and moderate to high doses of GC. Studies were identified in Medline and Embase. Results. 421 citations were screened, 3 were included. Male sex and ACPA-positivity were predictors of DAS remission. Female sex, long symptom duration, high baseline DAS and HAQ-scores, high BMI, and low response to GC at 2 weeks lowered odds of DAS remission. Predictors of insufficient improvement in HAQ functional ability were high baseline RAI, HAQ and VAS pain. Population and treatment characteristics, outcome variables and variables used to adjust for, differed among studies. Conclusion. Currently, not enough evidence is available to accurately predict therapy response and remission on an individual level. The important negative predictive value of early GC response confirms the importance of rapid re-evaluation after treatment initiation. Previously identified markers of poor prognosis and rapid radiological progression seem ineffective in predicting outcomes of intensive remission induction treatment in patients with early RA. Further research is necessary to develop a reliable predictive model.