Background/Purpose: Janus Kinase (JAK)/Signal Transducers and Activator of Transcription (STAT) is not only involved in IL23- signaling, but rather implemented into a broad range of cytokine pathways. So far, most data on the molecular impact of JAK inhibition on immune cells were taken from isolated in vitro stimulation cells and. Specific changes in patients with PsA before and after treatment with JAK inhibitors in vivo have not been addressed. In a longitudinal study, we provide first data upon the effects of JAK inhibition upon circulating immune cells in a cohort of PsA patients.

Methods: 25 patients fulfilling the CASPAR classification criteria of PsA were included in the study. Peripheral blood mononuclear cells (PBMCs) were purified from 25 patients before and after an average of 16 weeks of treatment with tofacitinib (TOF). Clinical and laboratory parameters were collected, and disease activity score 28 (DAS28), disease activity in psoriatic arthritis (DAPSA), minimal disease activity score (MDA) were calculated. Immune cell profiling was performed on PBMCs before and after therapy by mass cytometry (CyTOF), addressing the major subtypes of IL17-producing cells (monocytes, T cells, natural killer cells and innate lymphoid cells). Single cell RNA-seq (scRNA-seq) was additionally performed before and after therapy to address the transcriptional profile of circulating immune cells.

Results: All patients had active PsA at the time of enrollment (DAS28 median 3.52, SD±0.8 and DAPSA median 20, SD±6.1). The DAPSA score dropped to remission level in 20% of patients, while 40%, 32% and 8% ended to have low, moderate and high disease activity, respectively. DAS28 showed similar distribution of responses. MDA was reached in 28% of the patients. CyTOF analysis did not show significant changes in cell frequency before and after treatment nor did it relate to DAPSA and DAS28 response. However, qualitative differences on transcriptional level were identified by scRNA-seq. Cell prioritization analysis showed CD4⁺naïve T cells and CD14⁺monocytes as the immune cells mostly affected by JAK inhibition. Differential gene expression showed an increase of downregulated genes with a downregulated/upregulated ratio of 1.4 in the CD4⁺naïve T cells, whereas monocytes had a ratio of 0.9.

Among the top dysregulated pathways in CD4⁺naïve T cells, we found a downregulation of genes involved in the Th17 differentiation as well as tumor necrosis factor (TNF), NFkB and JAK/STAT pathways. These changes in CD4⁺naïve T cells were associated with downregulation of apoptotic signaling and upregulation of metabolic pathways. Among them, oxidative phosphorylation was associated with the highest normalized enrichment score as compare to glycolysis.

Conclusion: JAK inhibition induced a different gene expression profile in circulating immune cells with prominent downregulation of pro-inflammatory pathways in CD4⁺naïve T cells as well as a shift in their metabolic signaling towards a more quiescent state.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/jak-inhibition-re-balances-gene-expression-profile-of-circulating-immune-cells-in-patients-with-psoriatic-arthritis/