OP0030 TREATMENT OF NON-BIOLOGIC-DMARD-IR PSA PATIENTS WITH UPADACITINIB OR ADALIMUMAB RESULTS IN THE MODULATION OF DISTINCT FUNCTIONAL PATHWAYS: PROTEOMICS ANALYSIS OF THE SELECT-PSA 1 PHASE 3 STUDY
Authors: Sornasse T. , Anderson J. , Kato K. , Lertratanakul A. , Ritchlin C. T. , McInnes I. 
Published: May 2021

Background:

Treatment of non-biologic-DMARD-IR (DMARD-IR) PsA patients with upadacitinib (UPA) at 15 mg QD, an oral JAK1 selective inhibitor, resulted in improvement in musculoskeletal symptoms, psoriasis, physical function, fatigue, quality of life, and inhibited radiographic progression; improvements were observed as early as Week 2 (ACR20 and ACR50). UPA 15 mg QD was non-inferior to adalimumab (ADA) 40 mg EOW for ACR201

Objectives:

To determine the relative biological pathway modulation of UPA compared with ADA in patients with PsA via the evaluation of a pre-defined set of plasma proteins associated with inflammation.

Methods:

Patients from the SELECT-PsA1 study (DMARD-IR PsA patients) were randomly selected (PBO, n=100; UPA 15 mg QD, n=100; ADA 40 mg EOW, n = 100). The levels of 92 inflammation related protein biomarkers (pBM) were analyzed using a multiplexed Proximity Extension Assay platform in plasma samples collected at baseline, week 2, and 12; change from baseline in protein levels were expressed as Log2 Fold Change; a Repeated Measure Mixed Linear Model identified proteins modulated by UPA and ADA compared to Baseline. Functional pathway prediction was performed in silico with a commercially distributed software where 52 significantly modulated pBM (mean |Log2 FC| ≥ 0.1 AND FDR ≤ 0.05) were selected; results were summarized based on 3 core biological groups: 1) adaptive immune system, 2) innate immune system, and 3) non-immune connective and vascular systems.

Results:

At the single pBM-level, at the week 2 and 12 time points, treatment with UPA 15 mg QD resulted in distinct down modulation of T cell-associated (CD5, CD8a, IL15Ra, SLAMF1, TRANCE) and myeloid cell-associated pBM (CSF-1, CCL7, CCL13) that was not observed in the ADA treated group. Reciprocally, treatment with ADA 40 mg EOW resulted in a specific down modulation of a subset of neutrophil associated pBM (CCL3, CCL4, and S100A12). Both treatments resulted in the down modulation of IFN-, IL6-, and TNF-related pBM (CXCL9, CXCL10, CXCL11, IL6, TNFRSF19, and TNSF14) suggesting a common node of activity related to these pivotal cytokine-signaling pathways.

Functional pathway prediction based on the pBM data revealed that treatment with UPA is preferentially associated with the inhibition of T cells, but also NK cells and lymphocytes, compared to the predicted effects of treatment with ADA. Treatment with UPA also preferentially inhibited pathways related to bone damage and angiogenesis, as compared to the predicted effect of treatment with ADA. Finally, both treatments were predicted to inhibit multiple pathways associated with the activity of myeloid cells and phagocytes.

Conclusion:

Consistent with previous observations in RA2, UPA is predicted to inhibit multiple functional pathways associated the pathobiology of PsA belonging to the general categories of adaptive and innate immunity but also non-immune vascular and connective tissue biology. In contrast, treatment with ADA appears to affect more specifically functional pathways associated with the innate immune system.

References:

[1]McInnes, I. et al. Annals of the Rheumatic Diseases 79, 16-17 (2020).

[2]Sornasse, T., Song, I.H., Radstake, T. & McInnes, I. Annals of the Rheumatic Diseases 79, 581-582 (2020).

Acknowledgements:

AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.

Disclosure of Interests:

Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Jaclyn Anderson Shareholder of: AbbVie, Employee of: AbbVie, Koji Kato Shareholder of: AbbVie, Employee of: AbbVie, Apinya Lertratanakul Shareholder of: AbbVie, Employee of: AbbVie, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, UCB, Grant/research support from: AbbVie, Amgen, UCB, Iain McInnes Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma