Background/Purpose: Current serological markers such as RF and ACPA are useful for early diagnosis and perhaps for screening people at risk, but there remains a high unmet need for biomarkers that are present in the earliest stages of RA. The 14-3-3η serum protein is an early complementary marker to RF/ACPA and generates a specific anti-14-3-3η auto-antibody response to the native protein, that can also be measured for diagnosis. This study documents the expression of 14-3-3η auto-antibodies, their diagnostic utility and their complementarity to the 14-3-3η protein in early RA diagnosis.

Methods: 14-3-3η auto-antibody levels were measured on the Meso-Scale-Discovery electro-chemiluminescent platform in 873 patients; 254 with early RA, 324 with established RA and 295 controls. RA patients had a rheumatologist-confirmed diagnosis and early RA patients were DMARD-naïve. Controls included 10 each of psoriasis, ulcerative colitis, type 1 diabetes, and SLE, 9 with Crohn’s; 5 each of Sjogren’s, scleroderma, multiple sclerosis, gout and osteoporosis; 65 ankylosing spondylitis, 50 osteoarthritis and 106 healthy subjects. RA patient and control samples were provided by the co-authors, representing multiple international centers. Serum 14-3-3η protein levels were previously determined in these subjects with a positive diagnostic cut-off of > 0.19 ng/ml. Two-tailed t-tests and Mann-Whitney u-tests were used to compare differences in autoantibody levels between early RA, established RA and controls groups. Post-hoc ROC curves were generated and diagnostic utility was estimated by area under the curve (AUC) analysis.

Results: Median 14-3-3η auto-antibody levels were significantly higher in early RA subjects at 536 U/ml (154-3011) compared to established RA (223 U/ml, 64-2058), healthy (234 U/ml, 123-919), OA (258 U/ml, 125-1421) and all controls (264 U/ml, 96-1421), p values were < 0.0001 for early RA and each group.  The ROC AUC for early RA versus healthy and all controls was 0.92 (95%CI 0.89 to 0.95; p <0.0001) and 0.85 (95%CI 0.82 to 0.89; p <0.0001), respectively. A best cut-off of 380 U/ml was determined based on the optimal specificity (93%) and sensitivity (77%) point on the ROC curve. The corresponding PPV and NPV were 0.97 and 0.63 and LR+ and LR- were 11.6 and 0.25. In early RA, 61% were positive for the 14-3-3η protein, 77% were positive for 14-3-3η auto-antibodies, 67% for RF and 67% for ACPA.  75% of the early RA patients were positive for either RF or ACPA and 81% for at least one of RF, ACPA or 14-3-3η. Especially notable, was that 91% of early RA patients were positive for either the 14-3-3η protein or its auto-antibodies, capturing 63% of RF/ACPA seronegative patients. A low Pearson correlation of r=-0.06 between the 14-3-3η protein and its auto-antibody titres in early RA further reinforces their high complementarity.

Conclusion: 14-3-3η biomarkers, alone and in combination with RF and ACPA identify a large proportion of Early RA patients, potentially allowing for earlier intervention and more favorable clinical outcomes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/91-of-early-ra-patients-are-positive-for-serum-14-3-3%ce%b7-or-its-auto-antibodies/