Systemic inflammation in psoriasis: Circulating immune cells and cytokines
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Psoriasis is a common, chronic inflammatory skin disease associated with arthritis and multiple comorbidities. Autoantigens in the skin elicit a response in cytotoxic T cells, leading to local inflammation and recruitment of Th1 and Th17 cells from the blood. There is a complex immunological interplay between cytokines and cells from the innate and adaptive immune system, creating self-sustaining amplification loops. Increased levels of inflammatory cytokines and cells have been detected in blood from psoriasis patients. This notion, together with mechanistic similarities in establishment of psoriatic and atherosclerotic plaques, probably contributes to the increased prevalence of cardiovascular disease in psoriasis patients, however, this link needs to be further elucidated. No cure for psoriasis exists, and treatments aim at amelioration of symptoms. If topical treatments or UV-light are not effective enough, systemic medication including methotrexate, ciclosporin, fumarate or acitretin can be tried. Biological drugs specifically targeting the key cytokines TNF, IL-12/23 and IL-17 are available if conventional treatment is insufficient or contraindicated. However, these newer drugs are not accompanied by similarly precise laboratory analyses to aid selection of a specific drug for individual patients. As adverse events and loss of effect can be encountered, the switching from original to cheaper biosimilar drug has been controversial. The overall aim of this thesis was to study the blood immune system in psoriasis during active inflammation and treatment with biological drugs, in the search for disease specific immune signatures and biomarkers. In Study I, Luminex® Technology was used to investigate if serum cytokine levels could reflect psoriasis activity. In Study II, we compared impact of switching from original TNF inhibitor infliximab to biosimilar CT-P13 in psoriasis patients, both evaluating clinical parameters and effect on peripheral blood cells and their intracellular signalling, measured by phosphoflow cytometry. In Study III, single cell analysis of blood immune subsets, with special emphasis on the T cell lineage and intracellular signalling, was explored by use of mass cytometry. In all studies, clinical parameters including Psoriasis Area and Severity Index and Dermatological Life Quality Index were incorporated in analyses. The results indicate that cytokine and single cell analysis of blood can be useful methods for describing the complex systemic immunological picture in psoriasis. In Study I, logistic regression revealed higher risk of having severe psoriasis with increased IL-17A. Increase of IL-2 positively correlated with improvement of PASI and DLQI. Moreover, increase of IL-5, IL-10, IL-12, IL-22 and GM-CSF correlated with treatment effect. In Study II, intracellular phosphorylation levels in peripheral blood mononuclear cells were increased in psoriasis patients compared to healthy controls. This increased signalling activity decreased during continued treatment with infliximab, but did not completely normalize despite clinical remission. Switching from original to biosimilar infliximab did not affect laboratory findings, like cell abundance and phosphorylation levels, or clinical parameters. Study III revealed that biological therapy of psoriasis facilitated a shift in the balance of Th1 and Th2 cells in blood, transition from naïve/effector to memory predominance, reduction of circulating Th17, Th22, Th9 and CD8 cells and enhancement of inhibitory PD-1 expression on T cells. In the monocyte compartment, changes in favor of reduced cardiovascular risk were observed. Intracellular phosphorylation of blood immune cells was higher in psoriasis patients compared to healthy controls and in non-responders to treatment compared to responders. In conclusion, multiple aberrancies in circulating cells and cytokines were detected in patients with severe psoriasis, confirming that systemic inflammation is a trait of psoriasis. Further research can highlight the role of cytokines and peripheral blood mononuclear cells as potential tools for stratification of patients for personalized treatment. Optimized therapeutic strategies might alter the chronic course of psoriasis with positive implications on quality of life and long-term comorbidities.
Består avPaper I: Serum cytokine measurements and biological therapy of psoriasis - Prospects for personalized treatment?. Solberg SM, Sandvik LF, Eidsheim M, Jonsson R, Bryceson YT, Appel S. Scandinavian Journal of Immunology. 2018 Dec; 88(6):e12725. The article is available in the thesis file. The article is also available at: https://doi.org/10.1111/sji.12725
Paper II: Phosphorylation of intracellular signalling molecules in peripheral blood cells from patients with psoriasis on originator or biosimilar infliximab. Aarebrot AK, Solberg SM, Davies R, Bader LI, Holmes TD, Gavasso S, Bryceson YT, Jonsson R, Sandvik LF, Appel S. British Journal of Dermatology. 2018 Aug; 179(2):371-380. The article is available in the thesis file. The article is also available at: https://doi.org/10.1111/bjd.16269
Paper III: Mass cytometry analysis of blood immune cells from psoriasis patients on biological therapy. Solberg SM, Aarebrot AK, Sarkar I, Petrovic A, Sandvik LF, Jonsson R, Bergum B, Bryceson YT, Appel S. European Journal of Immunology. 2021 Mar; 51(3):694-702. The manuscript is available in the thesis file. The published version is available at: https://doi.org/10.1002/eji.202048857