11 General introduction and outline - a phase of clinically silent autoimmunity (e.g. autoantibodies present) - clinically suspect arthralgia (CSA); i.e. inflammatory joint pain without arthritis - undifferentiated arthritis (UA); clinically overt arthritis but RA diagnosis not established yet - RA (early and established) [10,11] Nonetheless, some phases might not be apparent in all patients [12]. Figure 1 | overview of stages in RA development As one can imagine, the identification of seronegative at-risk individuals in the pre-clinical stage, thus before the onset of arthritis, is quite challenging. Therefore, most studies investigating this phase focus on seropositive at-risk individuals. In seropositive individuals, this pre-clinical at-risk phase is characterized by immune system activation, including autoantibody production and non-specific musculoskeletal symptoms, mostly arthralgia [13]. Individuals may also experience fatigue, pain, and transient swelling of the joints [14]. Interestingly, signs of systemic inflammation, such as circulating antibodies and high levels of C-reactive protein (CRP), can be found years before the onset of RA and signify an elevated risk of developing RA in the near future [15,16]. Before developing overt clinical arthritis both ACPA-positive and ACPA-negative patients may have a symptomatic stage, which is characterized by the presence of arthralgia and/or subclinical inflammation. In this 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 [17]. Diagnosing and classification of rheumatoid arthritis In daily practice, the diagnosis of RA is made by the judgement of a rheumatologist, rather than by specific diagnostic criteria. This is usually based on the recognition of the clinical symptoms, radiological features, and autoantibody status. For research purposes, the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for RA have been developed (Figure 2) [18]. 1
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