Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis

Abstract

Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40–50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA. Patients achieving low disease activity according to the Disease Activity Index for PsA (DAPSA) at 3 months were classified as responders. Baseline and 3-month CD4+ transcript profiling were performed, and novel signaling pathways were identified using a multi-omics profiling and integrative computational analysis approach. Using transcriptomic data at initiation of therapy, we identified over 100 differentially expressed genes (DEGs) that differentiated IL-17Ai response from non-response and TNFi response from non-response. Integration of cell-type-specific DEGs with protein–protein interactions and further comprehensive pathway enrichment analysis revealed several pathways. Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and the genes, RAC1 and ROCKs, are supported by results from prior research. Our detailed network and pathway analyses have identified the rewiring of Rho GTPase pathways as potential markers of response to IL17Ai but not TNFi. These results need further verification.

G-Trap Assay I: Small GTPases as sensitive immune response biomarkers for active bacteremia

“…59 Of relevance to this study, IL-17 is known to stimulate GTPase activation. 60,61 As shown in our correlation analysis of Patient #3, cytokine IL-17 is connected with several mediators such as IL-12, GM-CSF, IFNg, IL-1β, and TNF-a to exert its proinflammatory effect, also manifested by a robust GTPase signal. Excessive levels of IL-17, such as in Patient # 3 (peak expression on day 6 was 433.0 pg/ml; compared to controls 8.7 ± 11.7 pg/ml 62 ) are comparable to or exceeding levels detected in plasma and tissues during sepsis resulting in multiple organ damage and death.…”

“…The significant findings from the analysis of samples from a patient (#3), presenting a robust proinflammatory response, were that the convergence of type1 and type3 response cytokines induced robust downstream GTPase signaling. IL-17, which is known to stimulate GTPase activation; [61,62] was strongly correlated to IL-12, GM-CSF, IFN-g, IL-1β, and TNF-a upstream of a robust GTP loading to Rac1, Rap1, and RhoA. Excessive levels of IL-17, such as in Patient # 3 (peak expression on day 6 was 433.0 pg/ml; compared to controls 8.7 ± 11.7 pg/ml [63]) are comparable to or exceeding levels detected in plasma and tissues during sepsis resulting in multiple organ damage and death.…”

Defining imaging sub-phenotypes of psoriatic arthritis: integrative analysis of imaging data and gene expression in a PsA patient cohort

“…Furthermore, differential expression of circulating protein mediators of various immune pathways that correlated with PsA phenotype was reported [ 6 ]. Immunologic heterogeneity was suggested to underlie differences in response to biologic therapies among patients with PsA [ 7 ]. Collectively, these preliminary data support the existence of genetic/immunologic heterogeneity underlying the various PsA disease sub-phenotypes.…”

Unravelling the complexity of psoriatic arthritis on a journey towards precision medicine

“…One study integrated CD4+ T cell transcriptomics with protein data and identified a signaling pathway that strongly associates with IL-17 inhibitor (IL-17i) response. (84) In addition, a recent proof-of-concept study applied machine learning techniques to clinical data and identifi ed patient clusters that follow variable IL-17i response trajectories. (85) This study demonstrates that precision medicine does not necessarily imply using multi-omics, but that application of novel techniques to analyze less complex data can provide relevant insights.…”

“…( 83) BAFF is a cytokine essential for maturation, proliferation and survival of peripheral B cells, and increased circulating BAFF is associated with pSS, SLE and RA. (83,84) In the presence of BAFF, TLR ligation promotes B cell activation, classswitch, somatic hypermutation and plasma cell differentiation that can all promote harmful autoantibody generation. (85)(86)(87) As well as T cells and TLRs, deficiency in the complement system is important to include as a factor contributing to the existence of autoantibodies in AIRD.…”