10 CHAPTER 1 Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects 0.5-1% of the population worldwide [1,2]. The disease can occur at any age, but on average patients are 40-50 years of age when diagnosed. RA is characterized by symmetrical peripheral polyarthritis, commonly, but not solely, affecting the hands, feet, knees, or ankles. Signs and symptoms of arthritis are usually accompanied by systemic inflammation and other clinical manifestations. Furthermore, RA is associated with an increased risk of cardiovascular disease (i.e. atherosclerosis and vasculitis) and interstitial lung disease [3,4]. If left untreated the inflammatory process eventually results in joint destruction, in some cases resulting in severe disability [5,6]. RA has a big impact on both the affected individual and society. While some patients can reach remission, not all patients respond to treatment. In addition to the disease itself, this can result in loss of work productivity and impairment of social activities. Even those who do respond are subjected to life-long treatment with costly therapies, which poses a substantial (financial) burden on patients and society. Autoantibodies RA is a syndrome rather than one uniform disease and two main subtypes of RA can be distinguished based on the presence or absence of autoantibodies against specific antigens. This is referred to as seropositive and seronegative RA, respectively. The most notable autoantibodies in RA are IgM-rheumatoid factor (RF), which is directed against the Fc tail of IgG, and anti-modified protein antibodies (AMPAs), autoantibodies directed against various post-translationally modified proteins. A variety of AMPAs has been identified, of which anti-citrullinated protein antibodies (ACPAs), are the most prevalent. Between seropositive and seronegative RA some remarkable differences can be observed. For instance, in ACPA-positive patients disease onset occurs at a younger age and in these patients a more severe clinical disease can be observed than in ACPA-negative patients [7]. In line with this, both RF-positive and ACPA-positive patients also have lower remission rates after initiation of disease-modifying anti-rheumatic drug (DMARD) treatment and more joint damage, although clinical manifestations at diagnosis are often indistinguishable between seropositive and seronegative patients [8,9]. Stages In the evolution from healthy to full-blown RA, different disease phases can be discriminated (see also Figure 1): - an initial at-risk period (with genetic and/or environmental risk factors)
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