Cytokine and chemokine multiplex analysis-based exploration for potential treatment and prognostic prediction in large-vessel vasculitis: A preliminary observational study

Abstract

Large-vessel vasculitis (LVV) is subclassified into two phenotypes; Takayasu arteritis and giant cell arteritis. Although the pathogenesis of LVV is not fully established, IL-6−IL-17 axis and IL-12−IFN-γ axis play critical roles in the disease development. We aimed to clarify the association between the disease state and cytokine/chemokine levels, to assess disease course as prognosis and to predict regulators in patients with LVV using the blood profiles of multiple cytokines/chemokines. This retrospective analysis comprised 35 LVV patients whose blood were collected, and multiplex cytokine/chemokine analysis with 28 analytes was performed. The differences of cytokines/chemokines corresponding disease status, upstream regulator analysis, pathway analysis and cluster analysis were conducted using the cytokines/chemokines profile. Relapse-free survival rate was calculated with Kaplan-Meier analysis in the classified clusters. In the robust analysis, IL-4, CCL2/MCP-1, TNFSF13/APRIL, TNFSF13B/BAFF, CHI3L1 and VEGF-A levels were significantly changed after treatment. Untreated LVV patients demonstrated activation of NFκB-related molecules and these patients are potentially treated with JAK/STAT inhibitors, anti-TNF-α inhibitors and IL-6 inhibitors. Cluster analysis in active LVV patients revealed two clusters including one with high blood levels of IL-1β, IL-6, IL-17, IL-23 and CCL20/MIP-3. A subgroup of the LVV patients showed activated IL-17 signature with high relapse frequency, and JAK/TyK2 inhibitors and IFN-γ inhibitors were detected as potentially upstream inhibitors. Blood cytokine/chemokine profiles would be useful for prediction of relapse and potentially contributes to establish therapeutic strategy as precision medicine in LVV patients.

Systemic vasculitis: one year in review 2023

“…Recent literature also explored further biological therapeutic options for LVV. IL-6−IL-17 axis and IL-12−IFN-g axis play critical roles in the disease pathogenesis, and activation of IL-17 signature was associated with higher relapse frequency in LVV (37). This observation indicates IL-17 as a promising target for precision medicine in LVV therapy, as it is potentially suppressed by JAK inhibitors.…”

Is Erythrocyte Sedimentation Rate Necessary for the Initial Diagnosis of Giant Cell Arteritis?

“…The exact pathophysiology of GCA remains to be fully elucidated, but inflammation develops in the artery wall with the recruitment of T-cells and monocytes, which transform into macrophages and eventually into the so-called giant cells [ 16 ]. Macrophages and T-cells within these vasculitis lesions secrete a spectrum of proinflammatory cytokines which importantly include interleukin-1 beta and interleukin-6 [ 16 , 17 ]. These cytokines induce a systemic acute-phase response which includes hepatic CRP secretion; thus, systemic CRP mirrors systemic inflammation and there is a clear correlation between the severity of the inflammation and the systemic levels of CRP [ 18 ].…”

Changes in the molecular profiles of large-vessel vasculitis treated with biological disease-modifying anti-rheumatic drugs and Janus kinase inhibitors

“…TNF-α acts in conjunction with IFN-γ to stimulate macrophages and induce the production of monocyte chemotactic proteins, particularly CCL2, which recruits monocytes expressing CCR2 to form multinucleated giant cells that are characteristic of LVV ( 26 , 27 , 54 – 56 ). Elevated CCL2 serum levels after treatment with GC suggest that CCL2 may contribute to treatment failure in LVV ( 57 ). At the transcriptome level, TNF-α inhibition, like TCZ, could improve the residual gene signature compared to GC monotherapy ( 25 , 58 ).…”