Background Serum 14-3-3η is an RA diagnostic marker whose higher levels are associated with more severe disease. Extracelluar 14-3-3η has been reported to upregulate factors intimately linked to RA pathogenesis. Predictive biomarkers of RA therapy response are needed to assist with clinical management.
Objectives This study sought to examine the relationship between 14-3-3η serum expression and DMARD remission at year 1 in an early RA cohort.
Methods Serum 14-3-3η levels were measured in a cohort of 409 early RA patients; all patients were DMARD naïve at baseline and DAS at year 1 was available in 401 patients. Median patient age was 56 years and 73% were female. Response was defined by DAS remission at year 1, DAS-ESR<2.6. The relationship between serum 14-3-3η and response was investigated by univariate analysis using three 14-3-3η concentration cut-offs which were selected as follows: the reported manufacturer's (Augurex 14-3-3η ELISA) reference range ≥0.19 ng/ml as well as 2 and 4 times that level, namely ≥0.40 and ≥0.80 ng/ml. 14-3-3η's contribution to predicting response was analyzed by regression analysis controlling for baseline DAS. Multivariate stepwise regression assessed 14-3-3η positivity together with baseline DAS, disease duration, age and gender to identify independent predictors of remission.
Results At baseline, 67% (n=275) of the early RA patients were 14-3-3η positive using the 0.19 ng/ml cut-off. At a cut-off of 0.40 and ≥0.80 ng/ml, 229 (56%) and 288 (46%) of the patients were positive for 14-3-3η. After 1 year, 130 (32%) of 401 patients achieved DAS remission. Patients who achieved DAS remission had higher median (IQR) baseline DAS, [5.3 (4.5-6.2) vs 4.7 (3.9-5.7), p=0.0005] TJC28 [7 (3-10) vs 4 (2-8), p=0.0006], patient global assessment [56 (38-74) vs 50 (36-65), p=0.013] and ESR [32 (17-48) vs 25 (13-40), p=0.0027]. Fisher exact testing revealed that patients who were negative for 14-3-3η at either the ≥0.4 or the ≥0.8 ng/ml cut-points had a higher likelihood of (LR) and odds (OR) of achieving DAS remission: LR=3.4 p=0.0407, OR=1.5 (95%CI 1.0-2.3) and LR=4.0 p=0.0290, OR=1.5 (95%CI 1.0-2.4), respectively. Regression analysis accounting for baseline DAS further confirmed that those patients who are negative for 14-3-3η's based on either ≥0.4 or the ≥0.8 ng/ml cut-points are more likely to achieve remission: LR=4.2 p=0.04 and LR=4.9 p=0.03. Independent predictors of DAS remission as determined by stepwise multivariate analysis were baseline DAS (LR=12.0 p=0.005), 14-3-3η negativity (LR=5.6 p=0.02), and male gender (LR=8.5 p=0.004).
Conclusions 14-3-3η is a mechanistic biomarker that is believed to play a role in the pathogenesis of RA. This study demonstrates that early RA patients with 14-3-3η levels below 0.8 ng/ml are more likely to achieve DAS remission at year 1 in response to DMARD therapy. This may be in part explained by in vitro observations which demonstrates that 14-3-3η behaves as a more potent ligand with increasing concentrations that are well within the clinical biomarker expression range. Further studies are warranted to determine if this is a general phenomenon across all classes of therapy.
Disclosure of Interest D. van Schaardenburg: None declared, W. Maksymowych Consultant for: Augurex Life Sciences Corp, A. Marotta Employee of: Augurex Life Sciences Corp