Importance of early diagnosis. The early symptomatic phase of rheumatoid arthritis (RA) represents a unique window of opportunity for intervention. Inflammation predominates in this phase of the disease, making immune mechanisms involved in the pathogenesis more responsive to treatment (Figure 1).1 Earlier diagnosis enables early treatment, which is important in the preservation of function for the long term.

Diagnosis of RA relies on patient history, physical examination, laboratory testing, and radiographic evidence of joint damage. RA is a chronic autoimmune disease that causes pain, stiffness, swelling, and limited motion and function of many joints. While RA can affect any joint, the small joints in the hands and feet tend to be involved most often. Chronic inflammation sometimes can affect several other organs as well, leading to comorbidities. The most common comorbidities of RA (in order of prevalence) are:

  • Cardiovascular disease, in particular ischemic heart disease.2
  • Infections, most commonly tuberculosis.3,4
  • Mental health conditions, mainly anxiety and depression.5–8


Classification of RA. The American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 rheumatoid arthritis classification criteria are based on clinical presentation (synovitis and joint swelling), serology, acute-phase reactants, and duration of symptoms (Figure 2).9 The criteria are designed to identify early-stage patients who are at high risk of persistent and/or erosive disease.9


Figure 11















Figure 29

file Ra














Measures of disease activities (Tables 1 and 2)10–14

  • The Disease Activity Score (DAS) and its derivatives, DAS28 (a 28-joint count) and DAS-CRP (using CRP [C-reactive protein] in place of ESR [erythrocyte sedimentation rate]), are widely used in randomized controlled trials.10,12
  • The advantage of providing a score for current disease activity rather than as a change score (as in ACR20, 50, and 70) makes the various DAS scores a “truer” reflection of the patient’s current disease status.12
  • The Simplified Disease Activity Index (SDAI) and an even further simplified version (no acute-phase reactant needed), the Clinical Disease Activity Index (CDAI), are strongly correlated with DAS.12
  • The RAPID3 (Routine Assessment of Patient Index Data) instrument was developed for the monitoring of patients in clinical care, given the ease of its use for both patients and rheumatologists.12,14


                                       Table 110,11                                                                                                                            Table 212




Laboratory tests

  • Laboratory testing can help in the differential diagnosis of RA versus other conditions that manifest with polyarthritis, such as osteoarthritis, and in the identification of subtypes of RA with different prognosis and response to treatment.
  • Rheumatoid factor (RF) and anti-citrullinated protein/peptides antibodies (ACPAs) are established biomarkers that are integrated into ACR/EULAR criteria for RA classification.9 The 14-3-3η protein is a newer marker for RA that has higher sensitivity in early RA than either RF or ACPAs and therefore can identify RA in some cases that are not identified using RF or ACPAs.15,16 CRP and ESR are serological acute-phase markers of inflammation that are also integrated into the ACR/EULAR criteria for RA classification.9

RF and citrullinated cyclic peptide (CCP) tests

  • The reported sensitivity of RF test is 57% for early RA17 and ranges from 60–86% for established RA.17,18 Specificity is relatively low (70–85%) for early and established RA.16,18–20 RF titer is most often assessed using latex agglutination or immunoturbidimetry, which primarily detects immunoglobulin (Ig) M RF. IgM RF, IgA RF, and IgG RF can also be measured individually with specific immunoassays.16,19 The presence of IgA RF, IgG RF, or both in patients with IgM RF and joint disease markedly increases the likelihood that the patient has RA.20
  • ACPAs appear long before signs of inflammation and immunity in the joints of some RA patients and are assessed by immunoassay with a filaggrin-derived CCP. The sensitivity of the CCP test is comparable to that of RF in early (59%)17 and established RA (64–88%).17,20 CCP is also highly specific (90–98%) for early and established RA.16,18,21,22


  • The 14-3-3η protein is elevated in serum and synovial fluid during joint inflammation.23 14-3-3η provides higher sensitivity for early RA than RF or CCP antibody testing. The addition of serum 14-3-3η measurement to RF and CCP antibody testing provides greater sensitivity for early RA. This increased sensitivity may translate into treatment earlier in the course of disease, which can minimize irreversible joint damage.15,16


  • CRP and ESR measurement can be used in combination with other laboratory and clinical results to identify patients with RA. CRP is produced by the liver in response to tissue injury, infection, and inflammation. Levels increase during periods of heightened RA disease activity, but elevations may also reflect inflammation due to other causes, such as infection or injury. The ESR typically rises 24 to 48 hours after an inflammatory stimulus and gradually returns to normal levels. ESR measurement may help assess disease activity when other clinical and laboratory studies yield equivocal results.




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