84 CHAPTER 4 It is clear that patients in the earliest stages of disease benefit the most from preventive strategies, and are more likely to have a delay or reduced risk of disease progression upon treatment, as demonstrated by the ARIAA and the PRAIRI study [77]. This points out that early identification of at-risk individuals is of paramount importance. This naturally leads to the need to define specific stratification criteria to select patients, as well as a redefinition of primary study outcomes. In addition, to delaying the onset or preventing RA, a secondary goal of therapy could be to improve quality of life in the preclinical phase of the disease, as was observed in the TREAT-EARLIER trial, and/or to positively alter the disease course if the patient does ultimately develop RA; for example, such a treatment might increase the likelihood to achieve DMARD-free remission or improve the health-related quality of life. Interestingly, in several trials (PRAIRI, ARIAA, and TREAT-EARLIER) certain beneficial effects persisted for ≥6 months after treatment cessation pointing towards the fact that control of inflammation very early in the disease course can result in long-lasting improvement of signs and symptoms. Of note, a good balance between under- and overtreatment is essential when developing preventive strategies in at risk individuals who are strictly speaking not yet patients, since they have not manifested clinical arthritis [78]. Furthermore, the type of intervention that is effective may also differ across the various preclinical phases of the disease. In the coming years research efforts should be steered towards better understanding the immune alterations in the preclinical phase of RA, for instance by investigating various compartments of the immune system, i.e. not only peripheral blood but also lymph nodes and the bone marrow. Early targeted intervention could result in beneficial effects larger than the effects of treatment initiated at the time of diagnosis (i.e. prevention of structural damage, reduced disability, higher (drug-free) remission rates, etc.). Numerous components of disease pathogenesis could serve as potential prevention targets, including autoantibody generation, inflammation and the immune response. Possible future treatment strategies are the delivery of tolerogenic therapies through nanoparticles, cellular therapies with tolerogenic antigen-presenting cells (i.e. dendritic cells), regulatory T cells and mesenchymal stem cells, immune checkpoint receptor agonists (i.e. PD-1, CD200R or BTLA stimulation) and co-stimulatory molecule blockade, as well as depletion strategies for (subsets of) T and B cells [79]. In summary, several preventive strategies have been shown to delay RA onset when applied in the early stages of the disease and to decrease disease burden at least temporarily, while true prevention has hitherto not (yet) been achieved. Results
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