Rheumatoid Arthritis (RA) is a chronic inflammatory disorder that typically affects cartilage and bone of small and middle-sized joints. Infiltration of the synovium by inflammatory cells causes... Show moreRheumatoid Arthritis (RA) is a chronic inflammatory disorder that typically affects cartilage and bone of small and middle-sized joints. Infiltration of the synovium by inflammatory cells causes destruction of cartilage, erosion of the adjacent bone and ultimately loss of function of the affected joint. Systemic inflammation, often going in parallel, can affect several organs and has long-term impact on organ function. This thesis presents work that investigates several aspects of basic immunological disease mechanisms with relevance to the inflammatory immune response in RA. Specifically, three main research questions triggered the experiments presented and form the outline of this thesis: 1. Do regulatory T cells feature anti-inflammatory properties besides the inhibition of effector T cells, which could help explain their therapeutic effectiveness in a murine model of established arthritis? 2. Are there specific features of the immune response to citrullinated antigens that could contribute to inflammation in RA, and can analysis of these features help in understanding the characteristics of anti citrullinated protein antibody producing B cells and their development? 3. Do certain genetic variants that associate with RA susceptibility contribute also to disease progression, as evidenced by the rate of joint destruction in RA? Show less
Results from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in... Show moreResults from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in patients with RA was validated in two cohorts indicating that predicting efficacy by a pharmacogenetic model is feasible in RA patients treated with MTX. Importantly, definitive conclusions about the role of genetic predictive factors in treatment outcome to DMARDS could not be drawn, since these results have to be further validated and replicated in future pharmacogenetic studies. Large randomized prospective studies should be planned to demonstrate its legitimate predictive and cost-effective value before a genetically individualized approach is applicable in daily clinical practice. The potential role of pharmacogenetics in the prediction of efficacy and adverse events in RA patients treated with DMARDs is presented in this thesis. Hereby, new knowledge is added to the relatively young research field of pharmacogenetics, which may hopefully lead to a better treatment strategy for RA patients Show less
