62 CHAPTER 4 Both ACPA-positive and ACPA-negative patients may have a symptomatic stage before developing overt clinical arthritis, which is characterized by the presence of arthralgia and/or subclinical inflammation and other circulating auto-antibodies in the seropositive patients. In the CSA phase, ACPA-positive and ACPA-negative patients have somewhat different clinical manifestations, with fewer tender joints but more rapid progression to RA in ACPA-positive patients [16]. The identification of seronegative at-risk individuals in the pre-clinical stage before the manifestation of arthritis is quite challenging and therefore most trials aimed at prevention of RA focus on seropositive at-risk individuals. In the time preceding disease manifestation and in the earliest stages of disease, T cells shift towards a pro-inflammatory phenotype, with accumulation of expanded T cells in the synovium and increased levels of serum pro-inflammatory cytokines, including IL-2 [17–20]. B lineage cells are also altered in pre-RA individuals, with high levels of IgA plasmablasts in the peripheral blood [21]. Moreover, patients develop anti-modified protein antibodies (AMPA) against post-translationally modified proteins, such as acetylated and carbamylated proteins, closer to disease onset [22,23]. These findings suggest that the immune system is already derailed years before RA onset, which would potentially allow for targeted interventions to prevent or at least delay disease onset. 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 radiographic progression [24]. Many patients also experience a rapid decrease in their work ability 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 [25]. Treatment in the preclinical phase of disease might lead to less complaints in the arthralgia phase, prevention of joint damage and improved work ability. In order to prevent disease development it is important to identify which patients would benefit the most from a targeted intervention since on average only 30% of seropositive individuals will develop RA, and since many different factors influence disease risk [26,27]. Family history of RA is associated with increased disease risk by three to ten times [28,29]. Genetic predisposition, such as the presence of specific alleles in the HLA-DRB1 locus called shared epitope (SE), and environmental exposure both have a role in disease risk [30]. One of the main disease risk factors in seropositive individuals is smoking which significantly increases the risk of progression towards RA (and this risk may persist for some years after smoking
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