with episcleritis, three patients had RA (3.5%), all of them females. The mean age of patients with rheumatoid episcleritis was 51 years (range 42Ð63 years); there were two cases with nodular episcleritis and one case with simple episcleritis; all of them were unilateral.

Although only about 10% of patients with episcleritis have an underlying connective tissue or vasculitic disease, RA is the most common diagnosis [121Ð123]. In our series of 85 patients with episcleritis, 15% had an underlying connective tissue disease or vasculitic disease; RA, AS, and arthritis associated with IBD were the most common diagnoses.

Bilateral episcleral nodules may occur in patients with concomitant active joint manifestations of RA (rheumatoid nodules) [149Ð152]; however, they also may appear in patients with inactive RA (rheumatoid nodulosis) [153] or in patients without any underlying disease (pseudorheumatoid nodules) [154Ð156].

Although keratitis, such as peripheral thinning, acute stromal keratitis, and sclerosing keratitis, may occur more frequently in rheumatoid episcleritis than in nonrheumatoid episcleritis, it is never severe [114]. Mild anterior uveitis occurs in a small minority of patients with rheumatoid episcleritis [114]. None of our three patients had either keratitis or anterior uveitis and none had changes in visual acuity.

6.1.1.4 Laboratory Findings

Although no laboratory tests are speciÞc for diagnosing RA, some of them are valuable in prognosis and management.

Rheumatoid Factor

The association of positive-serum rheumatoid factor with RA, initially described by Waaler, Rose, and others, is well-known [157, 158]. Rheumatoid factor is generally deÞned as an autoantibody (generally IgM, but also IgG and IgA) that reacts with certain epitopes in the Fc fragment of the IgG molecule. Approximately 70Ð90% of patients with deÞnite or classic RA have positive-serum RF (seropositive RA). Rheumatoid factor is also positive in the sera of a

lesser proportion of patients with other rheumatic diseases (SLE, scleroderma, and SjšgrenÕs syndrome), viral, bacterial, and parasitic infections, chronic inßammatory diseases, and neoplasms after chemotherapy or radiotherapy (see Table 3.8). Positive RF is also observed in healthy individuals during the course of secondary immune responses [159] and in 10Ð20% of nonrheumatic individuals over 65 years old who will not develop RA. The presence of rheumatoid factor does not establish the diagnosis of RA; the predictive value of the presence of rheumatoid factor in determining a diagnosis of RA is poor. Thus, fewer than one-third of unselected patients with a positive test for rheumatoid factor is found to have RA. Therefore, the rheumatoid factor test is not useful as a screening procedure. However, the presence of rheumatoid factor can be of prognostic signiÞcance because patients with high titers tend to have more severe and progressive disease with extraarticular manifestations [7, 10, 21, 160Ð165]. Rheumatoid factor is uniformly found in patients with nodules or vasculitis. In summary, a test for the presence of rheumatoid factor can be employed to conÞrm a diagnosis in individuals with a suggestive clinical presentation and, if present in high titer, to designate patients at risk for severe systemic disease.

Patients with rheumatoid scleritis usually have positive RF; RF titers are high in some of them [114].

Antibodies to Cyclic Citrullinated Polypeptides

Antibodies to cyclic citrullinated polypeptides (Anti-CCPs) can also be used to evaluate patients with RA. Although these antibodies are most commonly found in rheumatoid factor-positive patients, on occasion they can be detected in the absence of rheumatoid factor. In addition, the anti-CCP test has a similar sensitivity and a better speciÞcity for RA than does rheumatoid factor, and, therefore, some have advocated its use to evaluate RA patients instead of rheumatoid factor. This is particularly the case in individuals with early RA, in whom assessment of anti-CCP may be the most useful to conÞrm the diagnosis

and establish a likely prognosis. The presence of anti-CCP is most common in persons with aggressive disease, with a tendency for developing bone erosions. The development of anti-CCP is most frequent in individuals with an RA-associated HLA-b1 allele and in those who smoke cigarettes, and may occur before the development of clinical manifestations of RA. However, as with rheumatoid factor, the presence of anti-CCP is not useful to predict the future development of RA because it can be found in ~1.5% of normal individuals, most of whom will not develop RA, and occasionally in persons with other rheumatic diseases. However, it is a useful test to conÞrm a diagnosis of RA and to estimate prognosis.

Complete Blood Count

Patients with RA often have anemia, thrombocytosis, and eosinophilia. Suppression of proliferative synovitis may reduce or eliminate hematologic abnormalities.

Rheumatoid arthritis patients usually have normocytic hypochromic anemia that tends to follow the ESR, CRP levels, and activity of synovitis [166, 167]. The pathogenesis of the anemia seems to be related to ineffective erythropoiesis [167].

Mild thrombocytosis is often associated with RA. It also correlates with the ESR, CRP levels, activity of synovitis, and the presence of extraarticular manifestations [168]. The mechanism of thrombocytosis is unknown.

Eosinophilia (5% of total white blood cell count or greater) appears frequently in RA patients with severe deforming articular disease [169], pleuritic nodules, low complement levels, and high prevalence of vasculitis [170].

Acute-Phase Reactants

The ESR and the CRP level are elevated in almost all patients with RA, and generally these elevations correlate with disease activity [171Ð173]. Improvement in ESR and CRP on treatment indicates that a remission has been induced and that progressive joint destruction is retarded or prevented. The ESR is the most important laboratory criterionoftheAmericanRheumatismAssociation criteria for determining remission [174].

Patients with rheumatoid scleritis have higher ESR values than do RA patients without scleritis [114].

Synovial Fluid Analysis

The synovial ßuid in RA is usually turbid, with reduced viscosity, poor mucin clot formation, slightly decreased glucose concentration, and increased protein content. White cell count varies between 2,000 and 75,000; 50% or more of the cells are neutrophils. Total hemolytic complement (C3 and C4) in synovial ßuid is less than 30% of the usually normal serum complement, reßecting activation of the classic complement pathway by locally produced immune complexes [175]. Synovial histopathology may also be helpful in RA diagnosis.

Circulating Immune Complexes

Although the presence of CICs is not speciÞc to any particular disease, their detection may have some diagnostic and prognostic signiÞcance in RA. In early arthritis, CICs may be detected several months prior to the deÞnite diagnosis of RA [176]. The presence of CICs may help to distinguish seronegative RA from other arthropathies because CICs are found in 70% of patients with seronegative RA [177]. CIC levels may correlate with disease activity, although not as well as the ESR, CRP, or IgG RF [178]. Patients with rheumatoid vasculitis have high levels of CICs [31]. In our series of patients with rheumatoid scleritis, CICs were detected in all but two patients in which the test was done (16 patients). The mean titer of the CICs by Raji cell assay was 236 U/ml (normal, 0Ð50).

Antinuclear Antibodies

The frequency of ANAs in rheumatoid sera is about 40%, when measured by indirect immunoßuorescence. The most common pattern of ANA staining is the homogeneous pattern, which correlates with the presence of anti-DNAÐhistone antibodies. The second most common pattern of ANA staining is the speckled pattern, which correlates with the presence of a variety of antibodies directed against nonhistone nuclear proteins; these