14 CHAPTER 1 However, it has been shown that early treatment initiation in RA patients improves disease signs and symptoms, with lower disease scores and improved physical functioning as well as reduced structural damage detected by radiography [35]. For instance, in the “Prevention of RA by Rituximab” study (PRAIRI study) rituximab significantly delayed RA development, but was unable to prevent the risk of RA development [36]. Early treatment with abatacept showed improvement of subclinical arthritis and reduced RA development [37]. Also, early intervention with methotrexate was only partly successful as it did not prevent RA, but was able to decrease joint inflammation and reduce disease-related symptoms [38]. Many patients also experience a rapid decrease in their workability before treatment initiation and although treatment was unable to reverse disease-associated disability, it stabilized the need for sick leave and prevented incapacity for work [39]. Treatment in the preclinical phase of the disease could lead to fewer complaints in the arthralgia phase, prevention of joint damage, and improved ability to work. Aim and outline of the thesis The overarching aim of this thesis is to gain more knowledge on the adaptive immune response in different phases of RA and in various locations; ranging from the early at-risk phase to clinically apparent RA, from studies in blood-only to other bodily compartments, and from T-cells to B-cells. This thesis consists of three parts: Part I of this thesis describes the behaviour of the adaptive immune responses at various sites of inflammation during RA. We aimed to find shared characteristics of the inflammatory process to could give us insight whether development of selective targeting would be an alternative to generalized immunosuppressive strategies. In Chapter 2, we use the earlier-mentioned NGS technology to quantitatively assess whether different T-cell clones dominate the inflammatory infiltrate at various sites of inflammation in RA, i.e. in blood, synovial tissue, and synovial fluid. In addition, different joints and different locations within one joint are compared. Furthermore, we analyze to what extent these different compartments share the same dominant T-cell clones. Since T- and B-cells closely interact in adaptive responses, in Chapter 3 we analyze to what extent different joints also share dominant B-cell clones. This research builds upon the research performed in Chapter 2, by investigating the same compartments but now for the distribution of B-cells. Part II of this thesis focuses on the earliest stages of RA (i.e. the at-risk phase, phase of clinically silent autoimmunity, CSA, and UA), as early intervention in at-risk
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