The optimisation of intensive treatment strategies in early Rheumatoid Arthritis

Introduction The last decades meant a revolution for the treatment of patients with early Rheumatoid Arthritis (RA). In the past, patients were treated conservatively and treatment was only intensified when disease escalated, leading to structural damage and functionality loss in many RA patients. Nowadays, it is clear that early, intensive treatment with a clear predefined treatment target leads to excellent clinical outcomes for the majority of patients with early RA. First of all, it is shown that the earlier the treatment is started in RA, the better outcome the patient has. However, no information on the current extent of treatment delay was available for Flanders before this thesis. Secondly, many attempts are made to tailor treatment to an individual patient based on prognostic factors, to improve further disease outcome such as structural damage. However, algorithms combining these prognostic factors to aid a physician in his treatment choice were not yet tested in daily practice. Thirdly, many intensive treatment options exist nowadays to treat a patient with early RA. Yet, debate is ongoing on the exact content of this intensive treatment. Objectives The objectives of this research project were to determine: the treatment delay, defined as the time between symptom onset and treatment initiation in Flanders the reliability of classical prognostic factors in daily clinical practice the optimal intensive treatment strategy for every patient with RA Results In chapter 1, we demonstrated that in Flanders only one on five of newly diagnosed RA patients are treated in a timely fashion. Patients expressing more severe disease characteristics at baseline seemed to present themselves earlier to the treating rheumatologist than those without. Moreover, a difference in treatment delay between the different types of rheumatology practices was found. Patients treated in academic and general hospitals showed longer treatment delays than those treated in private practices. Furthermore, patient-related delay contributed the most to overall treatment delay in Flanders. Further research showed that aside of clinical characteristics, psychosocial factors also contributed to this patient-related delay. More research is needed to unravel the patient’s help seeking behaviour. In chapter 2, we firstly showed that composite algorithms using classical prognostic markers to predict structural damage in patients with early RA could not be reliably used in daily practice. No patients that developed rapid structural damage could be correctly identified by using these composite algoithms. Further in chapter 2, we showed that a combination of classical DMARDs with a GC bridging scheme seemed more effective than DMARD monotherapy in achieving higher remission rates and less radiographic progression after two years of treatment in our observational early RA cohort. Patients in this cohort were selected by the treating physician based on the presence of classical prognostic factors to receive a more conservative therapy if the RA profile of the patient seemed less severe at baseline. Hence, classical prognostic factors seem at the moment unreliable to base treatment choice upon in daily practice. In chapter 3, we presented the results of the CareRA RCT, showing firstly that in patients with poor prognosis markers after 16 weeks of treatment DMARD combinations with a high or moderate dose glucocorticoid (GC) remission induction scheme were not superior to Methotrexate (MTX) only with a moderate dose GC remission induction scheme. The efficacy of the three compared treatment strategies was similar. Yet, the safety profile was more advantageous for MTX only with a moderate GC scheme. Furthermore, we showed that MTX monotherapy with a moderate dose GC remission induction scheme seems more efficacious than MTX monotherapy without GCs in patients presenting without poor prognosis markers after 16 weeks of treatment. Most remarkable was the comparable safety profile between both treatments. Lastly, we investigated the efficacy and safety in the CareRA trial after one year of treatment for both patients with or without poor prognosis. The results confirmed the findings at week 16. The overarching conclusion regarding the third objective of this thesis is thus that MTX with an initial moderate dose glucocorticoid remission induction scheme seems to fit all patients with RA, with a high efficacy and acceptable safety profile. Conclusion Firstly, treatment delay is found to be too long in Flanders. Secondly, current classical biomarkers are not reliable in daily practice to guide treatment choice. Thirdly, MTX only combined with an initial moderate dose glucocorticoid remission induction scheme is very efficacious and safe for all patients with RA. We hope to have added essential evidence for an improved treatment outcome for every patient with RA with this thesis.status: publishe