Cytokine clusters in rheumatoid arthritis: pathogenetic parallels

A. A. Baranov; N. A. Lapkina; L. B. Shubin; I. M. Vorontsova; P. A. Chizhov; O. V. Lebedev; T. A. Buydina; E. V. Nikitina; I. A. Gorohov

doi:10.33667/2078-5631-2026-12-38-44

Cytokine clusters in rheumatoid arthritis: pathogenetic parallels

A. A. Baranov, N. A. Lapkina, L. B. Shubin, I. M. Vorontsova, P. A. Chizhov, O. V. Lebedev, T. A. Buydina, E. V. Nikitina, I. A. Gorohov

https://doi.org/10.33667/2078-5631-2026-12-38-44

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Abstract

An imbalance in the production of pro- and anti-inflammatory cytokines plays a significant role in the pathogenesis of rheumatoid arthritis (RA). Seropositivity for IgM rheumatoid factor (RF) and/or antibodies to cyclic citrullinated peptides (ACCP) determines disease subtypes. The aim of the study. To conduct a cluster analysis of the profile of pro- and anti-inflammatory cytokines detected in the blood serum of RA patients with an advanced stage of the disease in comparison with healthy individuals, the presence of IgM RF and ACCP in patients. Materials and methods. The study included 154 RA patients (41 men and 113 women of middle age 56.0 [50.0; 64.0] years), disease duration 9.4 [3.0; 13.0] years), seropositive 129 (83.8 %) for IgM RF and/or 106 (68.8 %) ACCP with moderate or high (DAS 28-ESR – 5.40 [4.65; 6.00]) disease activity. Serum concentrations of interleukins (IL), tumor necrosis factor α (TNF-α), interferon-γ (INF-γ) and soluble CD 40 ligand (sCD 40L) were determined using multiplex technology. Hierarchical clustering of cytokines was performed in 20 healthy individuals and RA patients using Ward’s method. In RA, a comparison was made between seronegative and seropositive groups for IgM RF/ACCP. Results. In healthy individuals, the cytokine network exhibited a physiological organization. Cytokines were grouped into compact, well-defined modules with minimal cross-links between individual components. A dominant proinflammatory core of cytokines was absent, and a balanced cytokine network was observed. IL-4 and IL-10 formed an integral and stable part of the regulatory component. In RA, the cytokine network underwent a dramatic reorganization caused by systemic inflammation. The network architecture became significantly more complex and fragmented, with the formation of four highly stable modules. The first was composed of IL-1β and TNF-α; the second included the cytokines of the IL-17A, IL-17F, and IL-23 axis; the third included IL-6 and IFN-γ; and the fourth included IL-4, IL-10, IL-31, IL-33, and sCD 40L. Analysis of the cytokine hyperproduction diagram revealed the IL-33 cluster. In patients seronegative for IgM RF, four modules are formed. The first is formed by IL-17A, IL-23, IL-25, and IL-17F; the second by IL-1β and IFN-γ; the third includes IL-33, IL-6, and IL-10; and the fourth includes TNF-α, IL-31, sCD 40L, and IL-4. In the IgM RF-seropositive variant of RA, the network architecture became significantly more complex and fragmented. A greater number of modules were identified. The first was formed by IL-23 and IL-17F; the second by IL-1β, IL-25, and IL-17A. TNF-α was embedded in each of them. The third module included IFN-γ and IL-6, the fourth – IL-31 and sCD 40L, the fifth – IL-33 and IL-4. IL-10 is more similar to the first two. In the patient groups with and without ACCP, the component architecture was similar for both the seronegative and IgM RF-seropositive variants of the disease, with minimal differences. The most pronounced and clear differences between the compared groups were obtained when analyzing the patient groups with and without IgM RF and/or ACCP. Conclusions. The results of cluster analysis demonstrate significant differences in the cytokine network architecture in RA compared to the control group, with the identification of a distinct IL-33 cluster. Differences are also observed between seronegative and seropositive subtypes of the disease.