Background/Purpose We have previously reported pilot data that patients who are only positive for 14-3-3η auto-antibodies (AAb) and negative for the 14-3-3η protein have a lower radiographic trajectory over 3 years. 14-3-3η AAbs have been described as “protective” based on their currently understood mechanism of clearing “harmful” extracellular 14-3-3η protein. In this study, we investigated how 14-3-3η AAb plasma expression informs clinical variables at baseline and over 3 years in a substantial cohort of patients with early RA.

Methods Baseline serum 14-3-3η protein and AAb levels were measured in a cohort of 409 early RA patients; all patients were treatment naive at baseline. Median patient age was 56 years and 73% were female. 14-3-3η protein levels were tested using the Augurex 14-3-3η ELISA (cut-off ≥0.19 ng/ml) and 67% of patients were positive. 14-3-3η AAb levels were measured on the MSD ECL platform and using a diagnostic cut-off of 380 U/ml, 77% of patients were +ve. Patients were grouped into 4 groups: 1) Negative for both markers, 2) Positive for the 14-3-3η protein only, 3) Positive for the 14-3-3η AAb only and 4) Positive for both markers. Assessment of differences across these 4 groups was performed using Kruskal-Wallis Analysis of Variance (ANOVA) with Dunn’s post-hoc testing to identify differences between individual groups.

Results Across the four 14-3-3η biomarker expression groups (table), ANOVA revealed  significant differences in RF and CCP positive rates and titers (p<0.0001), baseline TSS, SJC28 and ESR (≤0.01). Patients who were only 14-3-3η auto-antibody positive had significantly lower positivity rates and titers of RF and CCP (p<0.0001).

Over the 3 years, 14-3-3η auto-antibody +ve patients had significantly lower radiographic progression compared to patients who were double positive (p=0.004). 14-3-3η auto-antibody +ve patients also had significantly greater changes in response to treatment in SJC28 (p=0.0004) and DAS28 (0.006) compared to the double positive patient group.

Conclusion At baseline, the combination of a positive 14-3-3η auto-antibody test and a negative 14-3-3η protein test is significantly associated with a less severe RA disease profile and a better prognosis in regards to radiographic progression, SJC and DAS outcomes at 3 years. This data supports a protective role for 14-3-3η auto-antibodies.