Background: Early diagnosis and treat-to-target strategies in RA improve clinical and radiographic outcomes. 14-3-3η is a soluble diagnostic biomarker that is involved in the pathogenesis of RA (1) including the potent activation of key signalling cascades such as the JAK-STAT pathway and whose initial expression coincides with a transition to synovitis. In undifferentiated arthralgia, 14-3-3η independently predicts the development of RA. In confirmed RA, 14-3-3η levels decrease with treatment response (2) and those changes are associated with clinical and radiographic outcomes, including the prediction of joint damage progression in patients who have achieved clinical remission. Upadacitinib (UPA), an oral JAK1-selective inhibitor, demonstrated significant and clinically meaningful improvements in RA vs. methotrexate (MTX) in the SELECT-EARLY phase 3 study (3).
Objectives: To determine the impact of treatment with UPA monotherapy 15 mg QD on the levels of plasma 14-3-3η and to explore its relationship with clinical measures in early MTX-naïve RA patients.
Methods: Patients from the SELECT-EARLY study were randomly selected (UPA n = 100; MTX n = 100) from the pool of patients with available plasma samples. 14-3-3η tests were performed at Augurex according to standard operating procedures. Concentrations (ng/mL) were log-transformed for analysis. Non-parametric correlations between biomarker data and clinical end points were derived using the Spearman method. Changes in 14-3-3η over time were compared using a Repeated Measure Mixed Linear Model. All statistical analyses were conducted in JMP 14.1 (SAS Institute).
Results: At baseline, 79% of patients were 14-3-3η positive (≥ 0.19 ng/mL) with similar levels in both arms. Baseline levels of 14-3-3η correlated significantly with baseline disease activity measures (CDAI ρ = 0.164, p = 0.042; DASCRP ρ = 0.222, p = 0.004; and SDAI ρ = 0.177, p = 0.028) but not with baseline mTSS (ρ =-0.021, p = 0.787); of note baseline mTSS were relatively low in this subset of early RA patients (median = 2, IQR [0 – 9.5]). Over time, 14-3-3η levels tended to be lower in both the UPA and MTX groups. However, only treatment with UPA for 24 weeks resulted in a significant decrease in circulating 14-3-3η (p = 0.0002) (Figure 1). In addition, at week 24 in the UPA arm, changes in 14-3-3η levels correlated significantly with changes in concurrent disease activity measures (Δ CDAI ρ = 0.264, p = 0.030; Δ DASCRP ρ = 0.267, p = 0.021; and Δ SDAI ρ = 0.267, p = 0.028) but not with change in mTSS (ρ =-0.186, p = 0.111). In contrast to UPA, the relatively small changes in 14-3-3η induced by MTX did not correlate with any clinical measures.
Conclusion: This study demonstrates that treatment with UPA 15 mg QD monotherapy for 24 weeks significantly reduces the levels of circulating 14-3-3η in MTX-naïve RA patients and that these changes correlate with clinical measures of disease activity. Although we were not able to detect a clear relationship between changes in 14-3-3η and rate of structural damage progression, we would like to hypothesize that the superior clinical activity of UPA over MTX on joint damage may be related to the significant reduction in 14-3-3η induced by UPA; this hypothesis should be tested in a larger RA cohort with a larger proportion of joint damage progressors.
References: Maksymowych WP et al. Arthritis Res Ther. 2014;16(2):R99.
Hirata S et al. Arthritis Res Ther. 2015;17(1):280.
van Vollenhoven R et al. Arthritis Rheumatol.;2018 (Suppl 10; vol.70).
Disclosure of Interests: Thierry Sornasse Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, Simran Chahal Shareholder of: Augurex Life Science Corp, Employee of: Augurex Life Science Corp, Yuan Gui Shareholder of: Augurex Life Science Corp, Employee of: Augurex Life Science Corp, Neeraja Nagarajan Employee of: Augurex Life Science Corp, Alan Friedman Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, Norma Biln Shareholder of: Augurex Life Science Corp, AbbVie Inc, Employee of: Augurex Life Science Corp
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