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
In this thesis clinical and immunological studies in patients with undifferentiated (UA) and rheumatoid arthritis (RA) are described. Depending on the study population 6-55% of the patients who... Show moreIn this thesis clinical and immunological studies in patients with undifferentiated (UA) and rheumatoid arthritis (RA) are described. Depending on the study population 6-55% of the patients who presented with UA actually fulfilled the criteria for RA as defined by the ACR in 1987 over time. In the first four years, radiographic joint damage, disease activity and HAQ were comparable in patients with RA presenting with UA and patients presenting with RA. Treatment of UA patients with methotrexate resulted in postponing progression to RA and retarding radiographic joint damage. In UA patients who had low/intermediate pretreatment ACPA-levels and were treated with methotrexate, the incidence of RA was lower than in patients with high levels. The disease activity score that was used in RA patients was validated in patients with UA. To identify which patient with UA will progress to RA, a prediction rule was developed. In patients with RA, treatment with TNF-alpha resulted in recovery of regulatory T cells. The importance of these regulatory T cells was emphasized in the strength of the anti-inflammatory response to the human cartilage glycoprotein 39 in healthy individuals: it even suppressed other pro-inflammatory responses, whereas patients with RA reacted with a pro-inflammatory response Show less
