Background/Purpose: Despite significant therapeutic advancements in rheumatoid arthritis (RA), a substantial proportion of patients (20-40%) remain unresponsive to current treatments, including targeted synthetic DMARDs. A deeper understanding of the molecular impacts of JAK inhibitors (JAKinibs) could aid in identifying patient subgroups more likely to respond.

Objectives:

1. To evaluate the molecular changes induced by JAKinibs in RA immune cells via ex vivo assays.
2. To identify subgroups of patients starting JAKinibs with distinctive circulating levels of the potentially modulated molecular signature previously identified.
3. To determine the relevance of that molecular signature as predictors of therapy response to JAKinibs.

Methods: Peripheral blood mononuclear cells (PBMCs) and neutrophils from 41 treatment-naïve RA patients were cultured for 24 and 12 hours, respectively, with autologous serum and baricitinib (JAKinib) at 10 micromolar concentration. Changes in PBMC and neutrophil proliferation, adhesion, and NETosis-derived products were quantified using specialized kits. Changes in the secreted inflammatory proteins by PBMC and neutrophils were assessed via proximity extension assay (PEA) technology (Olink), analyzing a 92-protein inflammation panel.
The proteomic signature identified as deregulated by effect of ex vivo treatments was then analysed in the serum of a new cohort of 34 RA patients starting JAKinib treatment, with the aim of evaluating its association with therapeutic response.

Results: Baricitinib significantly reduced PBMC and neutrophil proliferation and adhesion in 90% of RA patients along with NETosis induced by autologous serum. Autologous serum further induced inflammatory protein secretion, affecting cytokines, chemokines, and growth factors, which were also reversed by baricitinib treatment.
Using serum samples from a second cohort of 34 patients with active RA starting JAKinibs, unsupervised analysis of the specific immune-molecular signature modulated ex vivo by JAKinib, was carried out. Two clear groups of patients were identified, characterized by higher and lower levels of the molecular signature.
When examining the clinical in vivo response to JAKinibs in the cluster of patients with elevated baseline levels of baricitinib-modulated proteins, a significantly higher response rate was observed at 3 and 6 months compared to patients with low protein expression levels.

Conclusion: The molecular analysis of changes induced by JAK inhibitors through ex vivo assays revealed a specific immune-proteomic signature that could be valuable in identifying in vivo patient subgroups more likely to respond to these drugs.

Acknowledgements: Supported by EU/EFPIA IMI-JU 3TR, ISCIII (PI21/0591, CD21/00187 and RICOR-21/0002/0033), co-financed by European Union, and MINECO (RYC2021-033828-I/PID2022-141500OA-I00).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/an-immune-molecular-signature-specifically-modulated-by-jak-inhibitors-ex-vivo-may-serve-as-a-predictor-of-therapy-response-in-vivo-to-these-drugs/