Background/Purpose 14-3-3η is a mechanistic marker that up-regulates inflammatory and joint damage factors that are implicated in the RA pathophysiological process¹. It is a potent inducer of TNF-α and IL-6 and we have previously described that low 14-3-3η levels prior to the initiation of anti-TNF and tocilizumab therapy marks good EULAR response and DAS remission. There is an unmet need for mechanistic biomarkers that enhance prediction of response to therapy. We also recently described that lower baseline plasma 14-3-3η levels mark good EULAR response in an RA cohort treated with DMARDs. In this study we tested plasma levels in the same cohort at year 1 to determine whether a change in 14-3-3η expression from baseline informs the change in DAS28 and response to therapy. 

Methods Three hundred and 80 (380) patients from the Reade early RA cohort were assessed for 14-3-3η titres at baseline and at year 1 follow up. All patients were DMARD naïve at baseline, mean age was 54 years, 73% were female and median duration of symptoms was 4 months (IQR 2-7). Fisher’s Exact test was performed to assess the relationship between baseline to year 1 change in 14-3-3η and a Good EULAR response and DAS remssion (<2.6) at year 2 follow up. Spearman rank correlations were used to identify associations between change in 14-3-3η and change in DAS28. A nominal logistic regression, controlling for baseline DAS, was used to investigate if change in 14-3-3η is a predictor of Good EULAR response.

Results Mean (SD) year 1 plasma 14-3-3η levels [3.3 ng/ml (6.0)] were significantly lower than baseline levels [4.4 ng/ml (6.9)], p=0.0004 reflecting the modifiability of 14-3-3η plasma concentrations over this period. The change in 14-3-3η titres significantly correlated with the change in DAS from baseline to year 2 (r=0.12, p=0.02) across the whole cohort. The Fisher Exact test revealed that a decrease in 14-3-3η from baseline to year 1 was significantly associated with a Good EULAR response [LR = 4.4, OR(95%CI)=1.6 (1.1-2.4), p=0.023] and remission [LR = 4.5, OR(95%CI)=1.3 (1.0-1.7), p=0.022] at year 2. In a bivariate model controlling for baseline DAS28, a decrease in 14-3-3η, was an independent predictor of a Good EULAR response yielding an LR of 4.2, p = 0.04. Both baseline DAS28 (LR=15.6, p<0.0001) and the change in 14-3-3η (LR=5.1 p=0.024) were independent predictors of remission at year 2.

Conclusion 14-3-3η plasma levels decrease with DMARD therapy and their change correlates with the change in DAS28 and predict both a good EULAR response and DAS remission. These clinical findings align with the mechanistic understanding of 14-3-3η as a potent upregulator of inflammatory and joint damage factors and how a decrease in its expression corresponds with a reduced burden of disease.

Reference

1. Maksymowych, Walter P., et al. “14-3-3eta is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage.” Arthritis research & therapy 16.2 (2014): R99.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/change-in-14-3-3%ce%b7-expression-in-early-ra-patients-treated-with-dmards-corresponds-with-change-in-das28-and-good-eular-responses/