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A new serologic marker may help support the diagnosis of early rheumatoid arthritis (RA), particularly if used in conjunction with biomarkers already commonly measured, an international group of researchers reported.

Using a cutoff of 0.19 ng/mL of the marker known as 14-3-3-eta in serum, the area under the curve (AUC) was 0.89 (95% CI 0.85-0.93, P<0.0001), giving a sensitivity of 77%, specificity of 92.6%, and a positive likelihood ratio of 10.4 among patients with well established RA, according to , of the University of Alberta in Edmonton, and colleagues.

And using that cutoff among patients with early RA -- for patients whose median disease duration was only about 3 months and who had not received any disease-modifying treatments -- 64% of patients were serologically positive, compared with 57% being positive for rheumatoid factor (RF) and 59% for anti-citrullinated protein antibodies (ACPA), the two standard biomarkers used for diagnosis, the researchers reported in the November

The widespread recognition of the importance of early diagnosis and treatment of RA prompted the American College of Rheumatology and the European League Against Rheumatism in 2010 to revise their disease classification criteria, giving greater weight to the presence and titers of RF and anti-CCP antibodies.

However, some patients remain seronegative for one or both of those markers, particularly in early, undifferentiated disease, so additional markers have been sought to better predict risk and tailor therapy.

One potential candidate has been , which was identified at high concentrations in the synovium of patients with arthritis.

"Soluble 14-3-3-eta acts through signaling cascades such as the extracellular signal-regulated kinase and p38 pathway to upregulate proinflammatory cytokines, including interleukin (IL)-1-beta, IL-6, tumor necrosis factor-alpha, and factors that are involved in joint degradation such as matrix metalloproteinase (MMP)-9 and receptor activator of nuclear factor-kappa-B ligand (RANKL)," Maksymowych and colleagues wrote.

To evaluate the discriminatory ability of this marker in RA, the researchers enrolled 99 patients with early RA, 135 with established RA, and 385 controls who were healthy or diagnosed with another inflammatory disease such as ankylosing spondylitis and osteoarthritis (OA).

For early RA compared with healthy controls, the AUC was 0.81 (95% CI 0.76-0.87, P<0.0001). With a cutoff of 0.19 ng/mL, the sensitivity was 63.6%, specificity was 92.6%, and positive likelihood ratio was 8.6. The positive predictive value was 0.57 and negative predictive value was 0.78.

The marker also could help differentiate RA from OA, as was shown when the 0.19 ng/mL cutoff gave a sensitivity of 63.6%, specificity of 83.3%, and a positive likelihood ratio of 3.8.

In addition, when cutoffs of 40 ng/mL and 80 ng/mL were used for RA versus OA, specificities were 93.3% and 96.7%, while sensitivities were 59.6% and 49.5%.

When RF was combined with ACPA, the rate of identification was 72%, and when 14-3-3-eta was added to ACPA, the identification rate also was 72%. But when all three markers were used for early RA, the detection rate was 78%, and in established RA, the three markers together identified 96% of cases.

"Serum 14-3-3eta assessment enhanced the detection of RA over either RF or ACPA alone by 32% and 22%, respectively, in patients with early RA," the researchers observed.

Baseline levels of the 14-3-3-eta marker also correlated with disease severity, according to the researchers. Patients who were positive for this marker had higher baseline disease activity scores, at 6.3, compared with those who were negative (5.7, P=0.026), and had worse measurements on the Health Assessment Questionnaire (1.9 versus 1, P=0.001).

A previous study suggested that 14-3-3 may be independently associated with structural damage in both RA and psoriatic arthritis, "and because it has been shown to upregulate expression of MMP and RANKL, a prospective study is also warranted to examine its capacity as an independent predictor of radiographic progression," the researchers wrote.

These study findings suggest that further exploration of the utility of this biomarker is warranted, the authors stated.

"Through earlier and more accurate diagnosis of RA, patients can be provided earlier access to disease-modifying therapy to preserve joint function and minimize the economic and personal costs of RA," they concluded.

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