Serum 14-3-3η is a Novel Marker that Complements Current Serological Measurements to Enhance Detection of Patients with Rheumatoid Arthritis

Abstract

Objective.Serum 14-3-3η is a novel joint-derived proinflammatory mediator implicated in the pathogenesis of rheumatoid arthritis (RA). In our study, we assessed the diagnostic utility of 14-3-3η and its association with standard clinical and serological measures.Methods.A quantitative ELISA was used to assess 14-3-3η levels. Early (n = 99) and established patients with RA (n = 135) were compared to all controls (n = 385), including healthy subjects (n = 189). The sensitivity, specificity, positive and negative predictive values of 14-3-3η, and the likelihood ratios (LR) for RA were determined through receiver-operator curve analysis. The incremental value of adding 14-3-3η to anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) in diagnosing early and established RA was assessed.Results.Serum 14-3-3η differentiated established patients with RA from healthy individuals and all controls (p < 0.0001). A serum 14-3-3η cutoff of ≥ 0.19 ng/ml delivered a sensitivity and specificity of 77% and 93%, respectively, with corresponding LR positivity of 10.4. At this cutoff in early RA, 64% of patients with early RA were positive for 14-3-3η, with a corresponding specificity of 93% (LR+ of 8.6), while 59% and 57% were positive for ACPA or RF, respectively. When ACPA, RF, and 14-3-3η positivity were used in combination, 77 of the 99 patients (78%) with early RA were positive for any 1 of the 3 markers. Serum 14-3-3η did not correlate with C-reactive protein, erythrocyte sedimentation rate, or Disease Activity Score, but patients who were 14-3-3η-positive had significantly worse disease.Conclusion.Serum 14-3-3η is a novel RA mechanistic marker that is highly specific, associated with worse disease, and complements current markers, enabling a more accurate diagnosis of RA.

14-3-3η Autoantibodies: Diagnostic Use in Early Rheumatoid Arthritis

“…Serum14-3-3η proteinlevelsalsocorrelatedstronglywith the SF and serum levels of the matrix metalloproteinases MMP-1andMMP-3.Morerecently,wehavedemonstrated thattheserum14-3-3η proteinwaspresentatsignificantly higherlevelsinpatientswitherosiveRA 13 ,thatitwashighly specificforRA,andthatitwascomplementarytoRFand ACPAforRAdiagnosticsensitivity 14 .In vitro resultsdemon-stratedthatsoluble14-3-3η protein,atclinicallyrelevant concentrations,possessedligand-likepropertiesactivating intracellularsignaltransductioncascades,suchastheextracellularsignal-regulatedkinasesandJanuskinase/stress-activatedproteinkinases.Activationofthesepathwaysresulted in the convergence of signals within the nucleus and the correspondingupregulationofproinflammatorycytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α,andfactorsthatwereinvolvedinjointdegradation, suchasMMP-9andreceptoractivatorofnuclearfactor-κB ligand(RANKL) 13 .…”

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

“…Новым биомаркером РА является белок 14-3-3η (eta), повышение концентрации которого в сыворотке имеет оп-ределенное диагностическое значение и позволяет прогно-зировать прогрессирование деструкции суставов при ран-нем и развернутом РА [104]. Напомним, что 14-3-3η при-надлежат к семейству белков, включающих 7 изоформ, ко-торый регулирует активность широкого спектра внутри-клеточных белков [105].…”

14-3-3η in “Seronegative” Rheumatoid Arthritis

“…Because RF and ACPA are used in the 2010 American College of Rheumatology/European League Against Rheumatism RA classification criteria, we anticipate that future studies will reveal that the complementarity of 14-3-3η is underestimated in this study 3 because of the reliance on RF and ACPA in the criteria. Because immediate early referral to a rheumatologist is a central tenet in mitigating the debilitative aspects of this disease, the testing of 14-3-3η together with RF and ACPA may assist in identifying those patients who require an immediate early referral to a rheumatologist.…”