Upadacitinib Reduces Key Biomarker for Rheumatoid Arthritis

Thierry Sornasse, PhD

Upadacitinib could be a useful drug in treating patients with rheumatoid arthritis (RA) who are naïve to methotrexate.

In data planned for presentation during the European Congress of Rheumatology (EULAR) 2020 meeting, a team, led by Thierry Sornasse, PhD, AbbVie Immunology Clinical Development, determined the impact of treatment with upadacitinib monotherapy 15 mg once daily on the levels of plasma 14-3-3η, while also exploring the relationship with clinical measures in early methotrexate naïve rheumatoid arthritis patients.

The early diagnosis and treat-to-target strategies for rheumatoid arthritis are known to improve clinical and radiographic outcomes.

14-3-3η is a soluble diagnostic biomarker that is involved in the pathogenesis of RA including the potent activation of key signaling cascades such as the JAK-STAT pathway and whose initial expression coincides with a transition to synovitis.

However, for undifferentiated arthralgia, 14-3-3η independently predicts the development of RA and for confirmed RA, 4-3-3η levels decrease with treatment response 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, an oral JAK1-selective inhibitor, has shown significant and meaningful improvements for RA patients when compared to methotrexate in the SELECT-EARLY phase 3 trial.

The investigators randomly selected patients from the SELECT-EARLY trial from a pool of patients with available plasma samples. Of the 200 patients, 100 were given upadacitinib and 100 received methotrexate.

The team performed 14-3-3η tests and log0transmofrme concentrations for analysis. They also derived non-parametric correlations between biomarker data and clinical endpoints using the Spearman method and compared changes in 14-3-3η over time using a Repeated Measure Mixed Linear Model.

At baseline, 79% of the patient population was 14-3-3η positive (≥ 0.19 ng/mL) with similar levels in both arms.

The investigators found baseline levels 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).

On the other hand, 14-3-3η baseline levels did not correlate with baseline mTSS (ρ =-0.021, P = 0.787).

In addition, baseline mTSS were relatively low in the subset of early RA patients (median = 2, IQR [0 — 9.5]).

The investigators also found over time, 14-3-3η are lower in both treatment groups, but only 24 weeks of upadacitinib resulted in a significant decrease in circulating 14-3-3η (P = 0.0002).

The investigators also found at week 24, patients in the upadacitinib arm had changes in 14-3-3η levels that 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).

On the other hand, there were relatively small changes in 4-3-3η induced by methotrexate, which did not correlate with any clinical measures.

“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,” the authors wrote. “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.”

The study, “Correlation Of Plasma 14-3-3H Levels With Disease Activity Measures in Methotrexate-Naïve RA Patients Treated With Upadacitinib Monotherapy In The SELECT-EARLY Phase 3 Study,” was published online by EULAR.