Tumor necrosis factor alpha stimulation of macrophages, but not IL-6, promotes the secretion of 14-3-3η into the extracellular space through a TNF alpha-dependent necroptotic mechanism.

A 2021 systematic literature review published by authors from the University Hospitals of Morecambe Bay NHS Foundation Trust in the United Kingdom conclude the following about the 14-3-3n biomarker: Exogenous 14-3-3η stimulation has been reported to stimulate various cell types including macrophages, monocytes, and fibroblast-like synoviocytes activating key cell signalling cascades including: Stimulation of cells by extracellular 14-3-3η has been reported to increase key factors relevant to the pathophysiology of rheumatoid arthritis, including: Exogenous stimulation of human fibroblast-like synoviocytes, in a dose dependent manner, resulted in the development of invadosomes.

Taken together, extracellular 14-3-3η upregulates pro-inflammatory factors directly that are targeted with small molecules and/or biological Disease-modifying antirheumatic drug (DMARDs), including TNF, IL-6 and Janus kinases.

Golimumab Etanercept Certolizumab Inflixamab Inflectra Sarilumab Upadacitinib Baricitinib Ruxolitinib Fedratinib The body of independent evidence supporting the clinical utility of 14-3-3η continues to expand.

As shown in the table above, a number of studies have evaluated the specificity, sensitivity and value of 14-3-3η in combination with rheumatoid factor (RF) and/or the anti-cyclic citrullinated protein (ACPA, anti-CCP).

14-3-3η has been described as a modifiable marker, with post-treatment levels having been reported to decrease, stay the same, or in some cases increase despite patients being treated with different classes of therapy including small molecule and biological DMARDs like Methotrexate, Adalimumab, Tocilizumab, Tofacitinib and Upadacitinib.

As earlier detection of RA is often associated with better clinical outcomes, evaluating how 14-3-3η informs risk of disease onset in asymptomatic patients is and will continue to be of paramount importance to investigate.