Prevalence and significance of serum 14-3-3η in juvenile idiopathic arthritis.

BACKGROUND: Prompt diagnosis of juvenile idiopathic arthritis (JIA) is important to avoid long term complications. Elevated serum 14-3-3η levels improve the diagnostic sensitivity of rheumatoid factor (RF) and cyclic citrullinated peptide (CCP) antibody in adult rheumatoid arthritis (RA), and have been associated with more severe phenotype. We investigated the prevalence and clinical significance of serum 14-3-3η in different types of JIA. METHODS: JIA patients (n = 151) followed by the Pediatric Rheumatology Core at Children's Hospital of Los Angeles were categorized into 5 groups: polyarticular JIA RF+ (PJIA RF+; n = 39), PJIA RF- (n = 39), psoriatic arthritis (PsA; n = 19), enthesitis-related arthritis (ERA; n = 18), and oligoarticular JIA (OJIA [control group]; n = 36). RF, CCP antibody, and 14-3-3η were measured for all patients. 14-3-3η serum levels > 0.2 ng/mL were considered positive. Disease activity was assessed by the Juvenile Arthritis Disease Activity Score-71 (JADAS-71). RESULTS: Elevated 14-3-3η levels were detected in 34/151 (23%) patients, and across all groups tested. Most patients with 14-3-3η had titers ≥4 times above the cutoff value. The majority (22, 65%) of 14-3-3η-positive patients were also positive for RF or CCP antibodies, 16 (47%) were positive for all 3, and 12 (35%) were single-positive for 14-3-3η. The highest prevalence of 14-3-3η was in PJIA RF+ patients (49%), followed by OJIA (22%). Positivity for 14-3-3η was not significantly associated with disease activity or age at diagnosis. CONCLUSION: Serum 14-3-3η can be detected in all forms of JIA tested but appears to be most common in PJIA RF+. 14-3-3η does not appear to correlate with disease activity in JIA.

Serum 14-3-3η is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis.

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.

Thrombopoietin levels in patients with disorders of platelet production: diagnostic potential and utility in predicting response to TPO receptor agonists.

Thrombopoietin (TPO) is the major regulator of megakaryopoiesis. Measurement of serum TPO levels may help distinguish between various causes of thrombocytopenia and predict treatment response to TPO receptor agonists. Serum TPO levels from 118 healthy volunteers and 88 patients with abnormal platelet counts were measured using a quantitative ELISA assay. The mean (range) TPO level in healthy volunteers was 39 (7-99) pg/mL. TPO values were correlated with the patient's diagnosis, platelet count, and response to TPO receptor agonists. 88 patients with history of consumptive thrombocytopenia (39) or hypoproliferative thrombocytopenia (49) were analyzed. Median (interquartile range) TPO level for consumptive thrombocytopenia patients was 63 (48-98) pg/mL with a corresponding median (interquartile range) platelet count of 73 (28-146) × 10(9) /L. In contrast, hypoproliferative thrombocytopenia patients had platelet counts [59 (30-117) × 10(9) /L] comparable with consumptive thrombocytopenia patients, but significantly higher serum TPO levels [706 (358-1546) pg/mL, P < 0.0001]. Analysis of 21 ITP patients treated with TPO receptor agonists demonstrated that a TPO level >95 pg/mL was associated with lack of clinical response (P < 0.002). TPO levels may have diagnostic utility in discriminating between patients with hypoproliferative and consumptive thrombocytopenia. Elevated TPO levels in ITP patients may predict a poor clinical response to treatment with TPO receptor agonists.