Page 11 - THE EVOLUTION OF EARLY ARTHRITIS AND CARDIOVASCULAR RISK Samina A. Turk

RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which affects many persons (around 1% of the world population), especially females(1). RA is characterized by (mainly synovial) inflammation, that can occur in any joint and gives rise to symptoms such as pain, swelling and stiffness(2). The inflammation may also lead to destruction of bone and cartilage, causing functional limitations, and therefore poses a personal and socioeconomic burden(3;4). However, advances in anti-rheumatic treatment have led to a substantial improvement in clinical outcomes and many patients nowadays reach a state of low disease activity or even remission(5). It is critical to suppress the inflammation early for a good prognosis. Unfortunately, even with treatment, a complete cure of the RA is not yet possible(6-8). Therefore, efforts are underway to try to stop the development of RA before the diagnosis; i.e. in the at-risk phase. Once these interventions are successful, the primary prevention of RA comes within reach.
THE EVOLUTION OF RHEUMATOID ARTHRITIS
The pathology of RA does not suddenly start with the onset of clinical arthritis, but is preceded by an at-risk phase with variable symptoms and often autoimmunity before the appearance of clinical arthritis. There are different phases in the development of RA, which are presented in figure 1 (from phase A until F)(9). In the first phase there is an interaction between genetics (A) and environmental risk factors (B). For example, the frequency of the serotypes HLA-DR4 is higher in RA patients and polymorphisms on a number of loci are associated with the susceptibility of RA, like protein tyrosine phosphatase 22 and peptidylarginin deiminase 4(10;11). Even more interesting, from the viewpoint of intervention, are the environmental risk factors, as these can potentially be modified. Many environmental risk factors are suggested to contribute to the development of RA, of which smoking is best documented(8;12-14). The role of other factors is less clear, such as alcohol, sugar-sweetened beverages or red meat consumption(15-20). After the exposure to risk factors, a phase of pre-clinical auto- immunity can sometimes be identified. In phase C the RA autoantibodies, such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP), are produced. Studies have shown that these antibodies are often present years prior to the onset of arthritis(21;22). Especially the presence of both RF and anti-CCP is highly specific for the future development of RA(9). Some inflammatory markers can also be elevated in this phase, like C-reactive protein (CRP), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6)(23-27). In phase D symptoms like arthralgia and joint stiffness are present, without clinical evidence of arthritis. In phase E, patients develop undifferentiated arthritis, and finally some of these patients enter phase F where classical clinical features of RA are present. Not all patients pass through all of these phases, and sometimes phases occur in a different order(8).
GENERAL INTRODUCTION 1
9