Background The pathogenesis of RA involves multiple factors that potentiate the disease to varying degrees within and between patients along the disease course. In treating to target, clinicians personalize treatment strategies by patient, to achieve and maintain disease remission. 14-3-3η is a diagnostic, mechanistic marker that is involved in the pathogenesis of RA and directly and potently up-regulates IL-6.1 Biomarkers that inform disease-specific processes may guide the selection of specific therapies at different times throughout the course of disease to facilitate the achievement of clinical outcomes by inhibiting “real-time” immune response mechanisms.
Objectives The aim of this study was to evaluate the impact of 4 different therapies on 14-3-3η expression and to determine whether 14-3-3η predicts DAS28 remission.
Methods Serum 14-3-3η levels were measured in a cohort of 149 Japanese patients prior to the initiation of therapy (BL) and at year 1 (Yr1). Patients were treated with either adalimumab (ADA), methotrexate (MTX), tocilizumab (TCZ), or tofacitinib (TOF). The Wilcoxon matched-pairs signed-rank test was used to determine whether Yr1 levels were statistically different than BL values. Within each of the therapy groups, achievement of DAS remission <2.6 was determined and group differences were assessed by Mann-Whitney U-Test. ROC curve analysis was performed to identify the optimal 14-3-3η cut-point for DAS28ESR remission sensitivity and specificity in the TCZ group. Bivariate analysis controlling for baseline DAS28ESR was used to assess 14-3-3η's independence across the entire cohort and within each treatment group.
Results Patient details are shown in the table. The match pairs t-test revealed that 14-3-3η titres significantly decreased from BL to Yr1 across the entire cohort [0.70 (0.17-5.96) to 0.37 (0.11-1.82), p<0.0001] and within each therapy group: ADA [0.62 (0.16-4.66) to 0.38 (0.13-1.40), p<0.0001], TCZ [0.43 (0.15-8.40) to 0.27 (0.10-2.58), p=0.0007] and TOF [1.30 (0.21-9.46) to 1.26 (0.11-3.07), p=0.013]. In comparing 14-3-3η levels based on whether DAS28ESR remission was achieved at Yr1, only the TCZ group remitters had significantly lower BL and Yr1 levels than non-remitters. ROC curve analysis in the TCZ group for remission based on BL 14-3-3η measurement yielded a significant AUC of 0.72, p=0.009 with the optimal cut-off of ≤0.40 ng/ml delivering a sensitivity of 70% (95%CI: 51-85) and a specificity of 85% (95%CI:62-97) with an LR of 4.7. Bivariate modeling controlling for BL DAS28ESR revealed that both the BL DAS28ESR [LR=4.79, p=0.029] and BL 14-3-3η ≤0.40 ng/ml cut-point [LR=8.58, p=0.003] were independent predictors of Yr 1 remission.
Conclusions Serum 14-3-3η is a modifiable mechanistic marker and levels ≤0.40 ng/ml are associated with a higher likelihood of achieving DAS28 remission in response to tocilizumab treatment. 14-3-3η's independence from DAS28ESR in predicting remission makes 14-3-3η a useful tocilizumab response marker that should be further investigated.
Arthritis Rheum. 2014; 66 Suppl 11:1975.
Disclosure of Interest K. Hanami: None declared, S. Hirata Consultant for: Abbvie, Eisai, and Bristol-Myers Squibb, Speakers bureau: Abbvie, Eisai, and Bristol-Myers Squibb, A. Marotta Employee of: Augurex Life Sciences, (Co-inventor of 14-3-3η), Y. Tanaka Consultant for: Augurex Life Sciences Corp